{"gene":"SCARB1","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":1994,"finding":"SR-BI (SRB1/CLA-1/CD36L1) was cloned by expression from a CHO cell variant and identified as a new member of the CD36 family of membrane proteins. It binds acetylated LDL, oxidized LDL, and maleylated BSA with high affinity (Kd ~5 µg protein/ml), and unexpectedly also binds native LDL with high affinity, defining a second class (class B) of scavenger receptors.","method":"Expression cloning, direct binding and competition assays in CHO cells, Northern blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — expression cloning with direct binding assays, founding paper replicated extensively","pmids":["7520436"],"is_preprint":false},{"year":1996,"finding":"SR-BI is an HDL receptor: it binds HDL with high affinity, is expressed primarily in liver and nonplacental steroidogenic tissues, and mediates selective cholesterol uptake (transfer of cholesterol but not HDL outer-shell proteins to cells) by a mechanism distinct from the classic LDL receptor endocytic pathway.","method":"HDL binding assays, selective lipid uptake assays in transfected cells, tissue expression analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding and functional uptake assays in transfected cells, replicated extensively across labs","pmids":["8560269"],"is_preprint":false},{"year":1996,"finding":"SR-BI (SRB1) recognizes negatively charged liposomes and mediates endocytosis of apoptotic cells; CHO transfectants constitutively expressing SRB1 took up apoptotic cells and negatively charged liposomes, whereas cells expressing class A scavenger receptors (type I or II) could not.","method":"Stable CHO cell transfection, endocytosis assays with apoptotic cells and liposomes","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in transfected cells with clear phenotypic readout, single lab","pmids":["8549669"],"is_preprint":false},{"year":1997,"finding":"Adenovirus-mediated hepatic overexpression of SR-BI in mice results in virtual disappearance of plasma HDL and a substantial increase in biliary cholesterol, demonstrating that SR-BI directly mediates hepatic HDL cholesterol uptake and increases cholesterol secretion into bile.","method":"Adenovirus-mediated gene transfer in mice, plasma HDL measurement, biliary cholesterol quantification","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo adenoviral overexpression with quantitative metabolic readouts, replicated across multiple studies","pmids":["9163428"],"is_preprint":false},{"year":1997,"finding":"An alternative splice variant of SR-BI, designated SR-BI.2, differs in its putative cytoplasmic C-terminal domain. CHO cells transfected with SR-BI.2 cDNA expressed protein and acquired the ability to take up fluorescent lipid (DiI) from DiI-HDL, indicating functional selective lipid uptake activity.","method":"cDNA cloning, CHO cell transfection, fluorescent DiI-HDL uptake assay, Northern blot","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transfection with functional uptake assay, single lab","pmids":["9254074"],"is_preprint":false},{"year":2001,"finding":"Caveolin-1 negatively regulates SR-BI-dependent selective HDL cholesteryl ester uptake. Stable overexpression of caveolin-1 in RAW, J-774, and SR-BI-transfected CHO cells decreased selective HDL [3H]cholesteryl ether uptake by ~50-60% without altering cell-associated HDL. Caveolae depleted of cholesterol (by beta-cyclodextrin) facilitated SR-BI-dependent uptake, while excess cholesterol in caveolae inhibited it.","method":"Stable caveolin-1 overexpression, adenoviral gene transfer, [3H]cholesteryl ether selective uptake assay, blocking antibodies, beta-cyclodextrin treatment","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (overexpression, cholesterol depletion, blocking antibodies) in single lab","pmids":["11683884"],"is_preprint":false},{"year":2002,"finding":"SR-BI, but not CD36, efficiently directs HDL-derived cholesteryl ester (CE) to a neutral CE hydrolase pathway for hydrolysis at a metabolically active membrane compartment. HDL-CE hydrolytic activity was recovered in a membrane fraction. LDL-CE delivered by SR-BI was also hydrolyzed by neutral CE hydrolase, while CD36-delivered LDL-CE was processed by an acidic CE hydrolase, indicating distinct routing.","method":"In vitro CE hydrolysis assays with enzyme inhibitors, subcellular fractionation, comparison of SR-BI and CD36 transfected cells","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — multiple cell types and inhibitor-based mechanistic dissection, single lab","pmids":["12576515"],"is_preprint":false},{"year":2004,"finding":"SR-BI is localized in membrane rafts devoid of caveolin-1 in HepG2 hepatoma cells (demonstrated by detergent-free sucrose gradient fractionation). Both LDL-CE and HDL3-CE selective uptake in HepG2 cells occur via a retroendocytic pathway. Perturbation of membrane raft structure differentially affects LDL-CE vs HDL3-CE selective uptake.","method":"Detergent-free sucrose gradient fractionation, cholesterol oxidase/sphingomyelinase/filipin/beta-cyclodextrin treatments, retroendocytosis assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple membrane perturbation methods in single lab with functional readouts","pmids":["15226391"],"is_preprint":false},{"year":2004,"finding":"SR-BI is expressed in human intestinal enterocytes from week 14 of gestation, localized mainly over microvilli, and not associated with caveolin-1 or caveolae. Antisense knockdown of SR-BI in Caco-2 cells proportionally decreased free cholesterol uptake (without altering phospholipid or cholesteryl ester capture), and SR-BI antibodies lowered cholesterol uptake in intestinal organ culture.","method":"Immunofluorescence, immunogold electron microscopy, antisense transfection in Caco-2 cells, organ culture with blocking antibodies","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific phenotypic readout using multiple approaches, single lab","pmids":["14676281"],"is_preprint":false},{"year":2005,"finding":"The adaptor protein PDZK1 binds SR-BI (via its first PDZ domain) and controls hepatic SR-BI expression posttranscriptionally. PDZK1 is phosphorylated at Ser-509 by PKA (cAMP-dependent protein kinase); a S509A mutant PDZK1 lost the ability to upregulate SR-BI protein. Glucagon administration increased PDZK1 phosphorylation at Ser-509 and hepatic SR-BI levels while decreasing plasma HDL.","method":"Metabolic labeling, phosphoamino acid analysis, site-directed mutagenesis (S509A), in vitro PKA phosphorylation assay, phospho-specific antibody, in vivo glucagon treatment in rats","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + mutagenesis + in vivo validation, multiple orthogonal methods","pmids":["16174736"],"is_preprint":false},{"year":2006,"finding":"SR-BI-dependent selective cholesterol uptake and HDL resecretion (retroendocytosis) were quantitatively measured in COS-7 and HepG2 cells. The rate of SR-BI-dependent HDL retroendocytosis (~0.5 ng HDL/mg/min) was >30-fold slower than the rate of selective CE uptake (~17 ng HDL/mg/min) in COS-7 cells, demonstrating that the vast majority of SR-BI-dependent selective uptake occurs at the cell surface, not via retroendocytosis.","method":"Pulse-chase assay with biotinylated [125I]-HDL3, streptavidin precipitation, quantitative comparison of selective CE uptake vs. retroendocytosis rates","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative biochemical reconstitution approach, single lab","pmids":["16705213"],"is_preprint":false},{"year":2008,"finding":"SR-BI is required for normal glucocorticoid synthesis and LPS hepatic clearance. SR-BI-null mice showed glucocorticoid insufficiency due to primary adrenal malfunction from deficient cholesterol delivery from HDL, resulting in uncontrolled inflammatory cytokine response and markedly higher lethality in LPS-induced endotoxic shock. Corticosterone supplementation decreased LPS sensitivity in SR-BI-null mice.","method":"SR-BI knockout mice, LPS challenge, corticosterone supplementation rescue, ACTH stimulation tests, hepatocyte LPS clearance assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue experiment and multiple mechanistic readouts","pmids":["18064300"],"is_preprint":false},{"year":2009,"finding":"SR-BI binds to the engulfment adaptor protein GULP via its C-terminal intracellular domain (demonstrated by yeast two-hybrid and cell-free binding assay). SR-BI-GULP complex exists prior to activation. Upon PS binding, SR-BI activates GULP, which induces MAPK (p38 and ERK1/2) phosphorylation, which in turn activates Rac1-GTP, leading to actin cytoskeleton rearrangement and phagocytosis of apoptotic cells.","method":"Yeast two-hybrid, cell-free binding assay, co-immunoprecipitation, GULP siRNA knockdown, MAPK inhibitor treatment, Rac1-GTP pulldown assay","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Y2H, co-IP, cell-free binding, loss-of-function, inhibitors) establishing a defined signaling pathway","pmids":["19122200"],"is_preprint":false},{"year":2011,"finding":"C323 in the extracellular domain of SR-BI is required for HDL binding and cholesteryl ester uptake. C323G mutant SR-BI lost HDL binding and CE uptake activity. A blocking antibody against the C323 region inhibited HDL binding, directly implicating C323 as part of the HDL binding site. In C323G transgenic mice, plasma cholesterol regulation was impaired. Physiological levels of H2O2 upregulated SR-BI-mediated CE uptake by 65%, while GSH/DTT decreased it by 45%, indicating redox regulation via C323.","method":"Site-directed mutagenesis (C323G), blocking antibody, C323G transgenic mice, redox reagent treatment, CE uptake assays","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis + blocking antibody + transgenic mouse model with multiple functional readouts","pmids":["21917726"],"is_preprint":false},{"year":2012,"finding":"SR-BI mediates efferocytosis of apoptotic cells by binding phosphatidylserine and inducing Src phosphorylation and membrane recruitment, leading to downstream activation of PI3K and Rac1 for engulfment. Pharmacological inhibition of Src decreased PI3K, Rac1-GTP, and efferocytosis; Rac1 activation rescued defective efferocytosis in SR-BI−/− macrophages. Bone marrow transplantation showed hematopoietic SR-BI deficiency causes severely defective efferocytosis in atherosclerotic lesions.","method":"Bone marrow transplantation, in vitro/in vivo efferocytosis assays, Src/PI3K/Rac1 inhibitors, Rac1-GTP pulldown, SR-BI−/− macrophages","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo bone marrow transplantation + multiple pharmacological pathway dissections + rescue experiments","pmids":["26059978"],"is_preprint":false},{"year":2012,"finding":"Macrophage SR-BI regulates LPS-induced pro-inflammatory signaling. Bone marrow transplantation experiments showed SR-BI-null bone marrow enhances inflammatory response to LPS in wild-type recipient mice; WT bone marrow reduces response in SR-BI-null mice. SR-BI overexpression in J774 macrophages attenuated LPS-induced inflammation. The increased signaling in SR-BI-null cells was not related to changes in cellular cholesterol content and involved NFκB, JNK, and p38 pathways.","method":"Bone marrow transplantation, SR-BI overexpression in J774 cells, cytokine measurement, signaling pathway inhibitor studies","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal bone marrow transplantation + gain-of-function, single lab","pmids":["22589557"],"is_preprint":false},{"year":2014,"finding":"Discrete subdomains of SR-BI's extracellular (EC) domain, particularly in the N-terminal and C-terminal regions, are critical for HDL binding, HDL-CE selective uptake, free cholesterol efflux to HDL, and plasma membrane free cholesterol redistribution. This was shown using a panel of 16 SR-BI/CD36 chimeric receptors; changes in function were independent of receptor oligomerization status.","method":"SR-BI/CD36 chimeric receptor panel (16 constructs), transient expression in COS-7 cells, HDL binding assay, CE selective uptake assay, cholesterol efflux assay, plasma membrane cholesterol redistribution assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic domain-swap mutagenesis with multiple functional assays in one rigorous study","pmids":["25211142"],"is_preprint":false},{"year":2017,"finding":"SR-B1 is a silica receptor: through an extracellular α-helix, both mouse and human SR-B1 specifically recognize amorphous and crystalline silica (but not other nanoparticles). SR-B1-mediated silica recognition is associated with caspase-1-mediated (canonical) inflammasome activation in macrophages. SR-B1 genetic deletion and masking by monoclonal antibodies showed its requirement for silica-induced pulmonary inflammation in mice.","method":"Functional expression cloning, SR-B1 knockout mice, monoclonal antibody blockade, caspase-1 activation assays, murine pulmonary inflammation model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — expression cloning identification + genetic KO + antibody blockade + multiple cell types and in vivo model","pmids":["28147282"],"is_preprint":false},{"year":2017,"finding":"SCARB1 mediates cellular carotenoid uptake in birds. Wild-type SCARB1 promotes cellular uptake of carotenoids, but a splice donor site mutation in white recessive canaries causes abnormal splicing (loss of exon 4), producing a predominant isoform that lacks this function. Functional assays confirmed carotenoid uptake activity is lost in the mutant isoform.","method":"Genetic mapping, functional carotenoid uptake assays comparing wild-type and mutant SCARB1 isoforms, biochemical analysis of carotenoid tissue levels","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with wild-type vs. mutant isoform comparison + genetic mapping, single study","pmids":["28465440"],"is_preprint":false},{"year":2019,"finding":"SR-B1 in endothelial cells mediates LDL transcytosis across the endothelium to promote atherosclerosis. LDL co-localizes with SR-B1 in endothelial intracellular vesicles in vivo. Transcytosis requires direct LDL binding to SR-B1 and an eight-amino-acid cytoplasmic domain that recruits the guanine nucleotide exchange factor DOCK4. DOCK4 promotes SR-B1 internalization and LDL transport by coupling LDL binding to SR-B1 with RAC1 activation.","method":"In vivo vesicle co-localization, endothelial monolayer transcytosis assays, cytoplasmic domain deletion mutagenesis, DOCK4 recruitment assays, RAC1 activation assays, SR-B1 endothelial-specific knockout","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vivo colocalization, mutagenesis, GEF recruitment, RAC1 assay) in one rigorous study","pmids":["31019307"],"is_preprint":false},{"year":2019,"finding":"SR-B1 undergoes multimerization into large metastable clusters at the plasma membrane, which prevents its entry into endocytic pathways and is critical for its function. Multimerization requires the C-terminal leucine zipper of SR-B1 and actin polymerization; mutating the leucine zipper or disrupting actin caused rapid receptor internalization. The C-terminal PDZ-binding domain and cortical cytoskeleton attachment are not responsible for plasmalemmal retention.","method":"Single-chain variable fragment (ScFv) antibody-based live-cell imaging, single-molecule tracking, leucine zipper mutagenesis, actin polymerization inhibitors, endocytosis assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — novel live-cell imaging approach + mutagenesis + pharmacological perturbations with clear functional consequence in one rigorous study","pmids":["31231038"],"is_preprint":false},{"year":2021,"finding":"Macrophage SR-BI regulates autophagy via TFEB expression and recruitment of the VPS34-Beclin-1 complex. SR-BI deletion reduced PPARα-dependent TFEB expression and VPS34/Beclin-1 levels. Intracellular SR-BI localizes to autophagosomes, where it forms cholesterol domains that recruit Barkor and the VPS34-Beclin-1 complex. Overexpression of TFEB or VPS34 rescued defective autophagy in SR-BI−/− macrophages.","method":"SR-BI knockout macrophages, autophagosome fractionation, co-immunoprecipitation of SR-BI with VPS34-Beclin-1 complex, PPARα pathway analysis, TFEB/VPS34 overexpression rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO + subcellular fractionation + co-IP + rescue experiments with multiple orthogonal methods","pmids":["33661763"],"is_preprint":false},{"year":2022,"finding":"The splicing factor RBFOX2 maintains a specific Scarb1 isoform profile in mouse liver; decreased RBFOX2 function in diet-induced obesity causes a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. RBFOX2 binding to Scarb1 pre-mRNA was confirmed by enhanced iCLIP. Splice-switching oligonucleotides targeting this network alleviated obesity-induced liver inflammation and promoted an anti-atherogenic lipoprotein profile.","method":"Enhanced individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP), diet-induced obesity mouse model, splice-switching oligonucleotides, lipoprotein profiling","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — iCLIP direct binding + in vivo splice-switching rescue + multiple functional readouts","pmids":["36536133"],"is_preprint":false},{"year":2023,"finding":"Hepatocyte lipocalin-2 (Lcn2) improves HDL metabolism and alleviates atherosclerosis by blocking Nedd4-1-mediated ubiquitination of SR-BI at K500 and K508. Overexpression of Lcn2 attenuated atherosclerosis via SR-BI; hepatocyte-specific Lcn2 ablation had the opposite effect. Lcn2-improved HDL metabolism was abolished in SR-BI(K500A/K508A) mutation mice and in mice with hepatic SR-BI or Nedd4-1 deletion.","method":"Hepatocyte-specific overexpression and knockout mice, ubiquitination site mapping (K500/K508), SR-BI(K500A/K508A) knock-in mice, Nedd4-1 deletion mice, atherosclerosis quantification","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — site-specific ubiquitination mapping + multiple genetic models (KO, KI, conditional KO) with clear functional readouts","pmids":["37863040"],"is_preprint":false},{"year":2023,"finding":"Intestinal SR-B1 expression is regulated by the FXR pathway. Resveratrol intervention reduces fecal bile acid levels and FXR activity, suppressing jejunal SR-B1 expression via gut microbiome-mediated changes. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1 expression. Intestinal mucosa-specific SR-B1−/− mice on HFD showed improved lipid homeostasis and did not respond further to resveratrol intervention.","method":"Intestinal-specific SR-B1 knockout mice, Caco-2 cell treatment, fecal microbiota transplantation, bile acid quantification, FXR pathway analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — intestinal KO + cell-based mechanism + microbiota transplantation, single lab","pmids":["37160898"],"is_preprint":false},{"year":2012,"finding":"Cigarette smoke causes translocation and loss of SR-B1 from human keratinocytes through H2O2 production (primarily from NADPH oxidase activation). This effect was reversed by NOX inhibitors or catalase pretreatment. CS also caused formation of SR-B1-aldehyde adducts (acrolein and 4-HNE) and increased SR-B1 ubiquitination, contributing to receptor loss.","method":"Immunoblotting, immunoprecipitation, RT-PCR, confocal microscopy, NOX inhibitors, catalase pretreatment, aldehyde adduct detection","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, confocal, rescue by inhibitors) in single lab","pmids":["22442701"],"is_preprint":false},{"year":2008,"finding":"SR-BI-mediated HDL-CE delivery in the adrenal gland occurs at specialized plasma membrane compartments called microvillar channels. Formation of microvillar channels requires SR-BI expression and is regulated by ACTH. SR-BI forms homo-oligomers in the plasma membrane via its C-terminal region (demonstrated by FRET spectroscopy). SR-BI-mediated CE selective uptake is a two-step process: high-affinity HDL binding followed by CE transfer to the membrane.","method":"Electron microscopy of adrenal microvillar channels, FRET spectroscopy for oligomerization, ACTH regulation studies, SR-BI expression requirement experiments","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET-based oligomerization assay + electron microscopy localization + ACTH regulation, single lab review compiling primary data","pmids":["18840501"],"is_preprint":false}],"current_model":"SR-B1 (SCARB1) is a multispan membrane glycoprotein that functions as the primary HDL receptor, mediating selective uptake of HDL-derived cholesteryl esters into liver and steroidogenic tissues via a non-endocytic, cell-surface mechanism that requires specific extracellular subdomains (including C323) and is modulated by receptor multimerization through a C-terminal leucine zipper; it also facilitates bidirectional free cholesterol flux, LDL transcytosis across endothelium via DOCK4-RAC1 signaling, efferocytosis of apoptotic cells through a GULP-MAPK-Rac1 pathway (or Src-PI3K-Rac1 in macrophages), autophagy regulation via PPARα-TFEB-VPS34/Beclin-1, silica recognition triggering inflammasome activation, and carotenoid uptake; its expression and stability are controlled posttranscriptionally by PDZK1 (regulated by PKA phosphorylation at Ser-509) and by Nedd4-1-mediated ubiquitination at K500/K508 (counteracted by lipocalin-2), while alternative splicing regulated by RBFOX2 and redox modification of C323 further tune its function."},"narrative":{"mechanistic_narrative":"SCARB1 (SR-BI) is the principal cell-surface HDL receptor, a class B scavenger receptor that mediates selective uptake of HDL-derived cholesteryl esters into liver and steroidogenic tissues by a non-endocytic mechanism distinct from the LDL-receptor pathway [PMID:7520436, PMID:8560269]. It binds HDL with high affinity and transfers core lipid to cells without internalizing the lipoprotein particle; in vivo, hepatic SR-BI controls plasma HDL levels and biliary cholesterol secretion [PMID:9163428], and is required for HDL-dependent cholesterol delivery that sustains adrenal glucocorticoid synthesis [PMID:18064300]. Selective uptake is a two-step process — high-affinity HDL binding followed by CE transfer — that requires discrete extracellular subdomains including a critical C323 residue subject to redox regulation, with the bulk of CE transfer occurring at the plasma membrane rather than via retroendocytosis [PMID:16705213, PMID:21917726, PMID:25211142, PMID:18840501]. Surface retention and function depend on receptor multimerization into metastable clusters driven by the C-terminal leucine zipper and actin polymerization, which excludes SR-BI from endocytic pathways [PMID:31231038]. Receptor abundance and stability are tuned post-transcriptionally: the PDZ adaptor PDZK1 stabilizes hepatic SR-BI in a PKA/Ser-509-dependent manner [PMID:16174736], Nedd4-1 ubiquitinates SR-BI at K500/K508 to drive its turnover (antagonized by lipocalin-2) [PMID:37863040], and RBFOX2-controlled alternative splicing sets the hepatic isoform profile governing lipid homeostasis [PMID:36536133]. Beyond lipoprotein metabolism, SR-BI binds phosphatidylserine to drive efferocytosis of apoptotic cells through GULP–MAPK–Rac1 signaling and a Src–PI3K–Rac1 cascade in macrophages [PMID:19122200, PMID:26059978], couples endothelial LDL binding to transcytosis via a cytoplasmic DOCK4–RAC1 module [PMID:31019307], localizes to autophagosomes to recruit the VPS34–Beclin-1 complex via a PPARα–TFEB axis [PMID:33661763], and recognizes silica through an extracellular α-helix to trigger inflammasome activation [PMID:28147282].","teleology":[{"year":1994,"claim":"Established SR-BI as a distinct (class B) scavenger receptor, defining a new receptor class by showing it binds both modified and native LDL with high affinity.","evidence":"Expression cloning and direct binding/competition assays in CHO cells","pmids":["7520436"],"confidence":"High","gaps":["Did not identify the physiological ligand or the in vivo function","No structural basis for ligand binding"]},{"year":1996,"claim":"Identified SR-BI's physiological role as the HDL receptor mediating selective cholesterol uptake, distinguishing it mechanistically from the endocytic LDL receptor and resolving how cells acquire HDL core lipid.","evidence":"HDL binding and selective lipid uptake assays in transfected cells with tissue expression profiling","pmids":["8560269"],"confidence":"High","gaps":["Cell-surface vs. internalized site of CE transfer not yet resolved","Binding-site residues unmapped"]},{"year":1996,"claim":"Extended SR-BI ligand recognition beyond lipoproteins to anionic phospholipid surfaces, linking the receptor to apoptotic cell clearance.","evidence":"Gain-of-function endocytosis assays in stable CHO transfectants with apoptotic cells and charged liposomes","pmids":["8549669"],"confidence":"Medium","gaps":["Downstream engulfment signaling unknown","Single-lab gain-of-function without genetic validation"]},{"year":1997,"claim":"Demonstrated in vivo that hepatic SR-BI controls plasma HDL and routes cholesterol into bile, establishing its central role in reverse cholesterol transport.","evidence":"Adenoviral hepatic overexpression in mice with plasma HDL and biliary cholesterol quantification","pmids":["9163428"],"confidence":"High","gaps":["Overexpression rather than physiological levels","Mechanism of biliary secretion downstream of uptake not addressed"]},{"year":2002,"claim":"Showed SR-BI routes HDL-CE to a specific neutral hydrolase compartment distinct from CD36-mediated acidic routing, clarifying the intracellular fate of selectively taken-up lipid.","evidence":"In vitro CE hydrolysis assays with inhibitors and subcellular fractionation comparing SR-BI and CD36 transfectants","pmids":["12576515"],"confidence":"Medium","gaps":["Identity of the hydrolase/compartment not molecularly defined","Single lab"]},{"year":2004,"claim":"Resolved the membrane microenvironment of SR-BI, placing it in caveolin-1-independent rafts and extending its cholesterol-uptake function to intestinal enterocytes.","evidence":"Detergent-free fractionation, membrane perturbations, and antisense/antibody loss-of-function in HepG2 and Caco-2/organ culture","pmids":["15226391","14676281"],"confidence":"Medium","gaps":["Caveolin-1's regulatory role context-dependent and unresolved across cell types","Tissue-specific uptake mechanisms not unified"]},{"year":2005,"claim":"Defined post-transcriptional control of hepatic SR-BI by the PDZK1 adaptor through PKA phosphorylation, linking hormonal (glucagon) signaling to receptor abundance and plasma HDL.","evidence":"PKA kinase assays, S509A mutagenesis, phospho-specific antibodies, and in vivo glucagon treatment","pmids":["16174736"],"confidence":"High","gaps":["Molecular mechanism by which PDZK1 stabilizes SR-BI not detailed","Whether other tissues use this control unknown"]},{"year":2006,"claim":"Quantitatively settled that SR-BI-mediated CE uptake occurs predominantly at the cell surface, with retroendocytosis a >30-fold minor route.","evidence":"Pulse-chase with biotinylated [125I]-HDL comparing selective uptake and retroendocytosis rates in COS-7 and HepG2 cells","pmids":["16705213"],"confidence":"Medium","gaps":["Molecular machinery of surface CE transfer not defined","Single lab"]},{"year":2008,"claim":"Defined the structural and ultrastructural basis of selective uptake — homo-oligomerization via the C-terminus and ACTH-regulated microvillar channels — and a two-step binding/transfer model.","evidence":"FRET oligomerization spectroscopy, electron microscopy of adrenal microvillar channels, and ACTH regulation studies","pmids":["18840501"],"confidence":"Medium","gaps":["Compiled primary data, single lab","Functional necessity of oligomerization for uptake not isolated here"]},{"year":2008,"claim":"Established the physiological consequence of SR-BI-dependent cholesterol delivery to the adrenal, showing it is required for glucocorticoid synthesis and survival of endotoxic challenge.","evidence":"SR-BI knockout mice, LPS challenge, corticosterone rescue, and ACTH stimulation tests","pmids":["18064300"],"confidence":"High","gaps":["Whether SR-BI has direct anti-inflammatory roles independent of cholesterol delivery not separated here"]},{"year":2009,"claim":"Identified the cytoplasmic GULP–MAPK–Rac1 signaling axis through which SR-BI transduces phosphatidylserine recognition into actin-driven phagocytosis of apoptotic cells.","evidence":"Yeast two-hybrid, cell-free binding, co-IP, GULP knockdown, MAPK inhibitors, and Rac1-GTP pulldowns","pmids":["19122200"],"confidence":"High","gaps":["Cell-type generality vs. macrophage-specific pathways not reconciled","In vivo relevance not tested here"]},{"year":2011,"claim":"Mapped C323 in the extracellular domain as part of the HDL binding site and showed CE uptake is redox-regulated through this residue.","evidence":"C323G mutagenesis, blocking antibody, transgenic mice, and redox-reagent CE uptake assays","pmids":["21917726"],"confidence":"High","gaps":["Atomic structure of the binding site unresolved","Source/specificity of physiological H2O2 modulation in vivo unclear"]},{"year":2012,"claim":"Defined macrophage SR-BI as an in vivo efferocytosis receptor signaling through Src–PI3K–Rac1, demonstrating that hematopoietic SR-BI deficiency impairs apoptotic-cell clearance in atherosclerotic lesions.","evidence":"Bone marrow transplantation, efferocytosis assays, Src/PI3K/Rac1 inhibitors, Rac1 rescue, and SR-BI−/− macrophages","pmids":["26059978"],"confidence":"High","gaps":["Relationship between GULP-based and Src-based pathways not unified","Receptor proximal coupling to Src undefined"]},{"year":2012,"claim":"Showed macrophage SR-BI dampens LPS-induced inflammation independent of cellular cholesterol, implicating NF-κB/JNK/p38 signaling.","evidence":"Reciprocal bone marrow transplantation and J774 overexpression with cytokine and inhibitor studies","pmids":["22589557"],"confidence":"Medium","gaps":["Molecular mechanism linking SR-BI to NF-κB suppression unknown","Single lab"]},{"year":2012,"claim":"Demonstrated oxidative/electrophilic stress (cigarette smoke H2O2 and aldehyde adducts) drives SR-BI ubiquitination and loss, identifying environmental redox control of receptor stability.","evidence":"Immunoblot/IP, confocal microscopy, NOX inhibitors, catalase rescue, and aldehyde adduct detection in keratinocytes","pmids":["22442701"],"confidence":"Medium","gaps":["Ubiquitin ligase not identified here","Keratinocyte-specific relevance to lipoprotein metabolism unclear"]},{"year":2014,"claim":"Systematically mapped extracellular N- and C-terminal subdomains required for HDL binding, CE uptake, and bidirectional free-cholesterol flux, showing these functions are separable from oligomerization status.","evidence":"Panel of 16 SR-BI/CD36 chimeras with binding, uptake, efflux, and membrane cholesterol redistribution assays in COS-7","pmids":["25211142"],"confidence":"High","gaps":["No high-resolution structure to position the subdomains","How separate subdomains coordinate during transfer unknown"]},{"year":2017,"claim":"Identified SR-B1 as a silica receptor recognizing the particle via an extracellular α-helix and required for silica-induced inflammasome activation and pulmonary inflammation.","evidence":"Functional expression cloning, SR-B1 knockout mice, antibody blockade, and caspase-1 activation assays","pmids":["28147282"],"confidence":"High","gaps":["Coupling of surface silica binding to cytosolic inflammasome assembly undefined","Relationship to lipoprotein-binding subdomains unclear"]},{"year":2017,"claim":"Established SCARB1 as a carotenoid uptake transporter, using a natural splice mutation in canaries to show isoform-dependent loss of carotenoid transport.","evidence":"Genetic mapping and carotenoid uptake assays comparing wild-type and exon-4-deficient isoforms","pmids":["28465440"],"confidence":"Medium","gaps":["Mammalian relevance of carotenoid transport not addressed","Single study"]},{"year":2019,"claim":"Revealed an endothelial SR-B1 function — LDL transcytosis — driven by a cytoplasmic eight-residue motif recruiting DOCK4 to couple LDL binding to RAC1 activation and internalization, promoting atherosclerosis.","evidence":"In vivo vesicle colocalization, transcytosis assays, cytoplasmic deletion mutants, DOCK4 recruitment, RAC1 assays, and endothelial-specific knockout","pmids":["31019307"],"confidence":"High","gaps":["How transcytosis is reconciled with non-endocytic surface retention in other tissues unresolved","Regulation of DOCK4 recruitment unknown"]},{"year":2019,"claim":"Explained how SR-B1 avoids endocytosis: it multimerizes into metastable plasma-membrane clusters dependent on the C-terminal leucine zipper and actin, and this clustering is required for function.","evidence":"ScFv-based live-cell single-molecule imaging, leucine zipper mutagenesis, actin inhibitors, and endocytosis assays","pmids":["31231038"],"confidence":"High","gaps":["Stoichiometry of functional clusters undefined","How clustering interfaces with transcytosis machinery unclear"]},{"year":2021,"claim":"Connected SR-BI to autophagy regulation, showing intracellular SR-BI forms autophagosomal cholesterol domains that recruit the VPS34–Beclin-1 complex via a PPARα–TFEB axis.","evidence":"SR-BI knockout macrophages, autophagosome fractionation, co-IP of the VPS34–Beclin-1 complex, and TFEB/VPS34 rescue","pmids":["33661763"],"confidence":"High","gaps":["How SR-BI traffics to autophagosomes unknown","Relationship between surface receptor pool and autophagosomal pool unclear"]},{"year":2022,"claim":"Identified RBFOX2-controlled alternative splicing as a determinant of the hepatic Scarb1 isoform profile governing lipid homeostasis, exploitable with splice-switching oligonucleotides.","evidence":"iCLIP demonstrating RBFOX2 binding to Scarb1 pre-mRNA, diet-induced obesity model, and splice-switching oligonucleotide rescue","pmids":["36536133"],"confidence":"High","gaps":["Functional differences between the swapped isoforms not fully defined","Human relevance of the isoform switch not established here"]},{"year":2023,"claim":"Defined a Nedd4-1/lipocalin-2 axis controlling SR-BI degradation, mapping ubiquitination to K500/K508 and showing hepatocyte Lcn2 protects the receptor to improve HDL metabolism and limit atherosclerosis.","evidence":"Ubiquitination site mapping, SR-BI(K500A/K508A) knock-in, hepatocyte Lcn2 and Nedd4-1 conditional mice, and atherosclerosis quantification","pmids":["37863040"],"confidence":"High","gaps":["How Lcn2 mechanistically blocks Nedd4-1 access unresolved","Interplay with PDZK1 stabilization not integrated"]},{"year":2023,"claim":"Placed intestinal SR-B1 under FXR/bile-acid and microbiome control, linking dietary intervention to receptor expression and systemic lipid 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metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/36536133","citation_count":33,"is_preprint":false},{"pmid":"33398433","id":"PMC_33398433","title":"High HDL-Cholesterol Paradox: SCARB1-LAG3-HDL Axis.","date":"2021","source":"Current atherosclerosis reports","url":"https://pubmed.ncbi.nlm.nih.gov/33398433","citation_count":32,"is_preprint":false},{"pmid":"27651445","id":"PMC_27651445","title":"SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a).","date":"2016","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27651445","citation_count":32,"is_preprint":false},{"pmid":"18542840","id":"PMC_18542840","title":"The SCARB1 gene is associated with lipid response to dietary and pharmacological interventions.","date":"2008","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18542840","citation_count":30,"is_preprint":false},{"pmid":"16705213","id":"PMC_16705213","title":"Quantitative analysis of SR-BI-dependent HDL retroendocytosis in hepatocytes and fibroblasts.","date":"2006","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/16705213","citation_count":30,"is_preprint":false},{"pmid":"34072125","id":"PMC_34072125","title":"SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34072125","citation_count":29,"is_preprint":false},{"pmid":"23564696","id":"PMC_23564696","title":"Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice.","date":"2013","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/23564696","citation_count":29,"is_preprint":false},{"pmid":"28134663","id":"PMC_28134663","title":"SR-B1 and PDZK1: partners in HDL regulation.","date":"2017","source":"Current opinion in lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/28134663","citation_count":28,"is_preprint":false},{"pmid":"37644041","id":"PMC_37644041","title":"SCARB1 in extracellular vesicles promotes NPC metastasis by co-regulating M1 and M2 macrophage function.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37644041","citation_count":28,"is_preprint":false},{"pmid":"27242666","id":"PMC_27242666","title":"ACTH Regulation of Adrenal SR-B1.","date":"2016","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27242666","citation_count":27,"is_preprint":false},{"pmid":"28504304","id":"PMC_28504304","title":"Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR-B1.","date":"2017","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28504304","citation_count":27,"is_preprint":false},{"pmid":"24253048","id":"PMC_24253048","title":"The atherogenic Scarb1 null mouse model shows a high bone mass phenotype.","date":"2013","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24253048","citation_count":27,"is_preprint":false},{"pmid":"19420333","id":"PMC_19420333","title":"Morphologic and electroretinographic phenotype of SR-BI knockout mice after a long-term atherogenic diet.","date":"2009","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/19420333","citation_count":27,"is_preprint":false},{"pmid":"35107765","id":"PMC_35107765","title":"SR-B1's Next Top Model: Structural Perspectives on the Functions of the HDL Receptor.","date":"2022","source":"Current atherosclerosis reports","url":"https://pubmed.ncbi.nlm.nih.gov/35107765","citation_count":26,"is_preprint":false},{"pmid":"29976771","id":"PMC_29976771","title":"Hepatocyte-Specific SR-BI Gene Transfer Corrects Cardiac Dysfunction in Scarb1-Deficient Mice and Improves Pressure Overload-Induced Cardiomyopathy.","date":"2018","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29976771","citation_count":26,"is_preprint":false},{"pmid":"28363797","id":"PMC_28363797","title":"Scavenger receptor class B member 1 (SCARB1) variants modulate hepatitis C virus replication cycle and viral load.","date":"2017","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/28363797","citation_count":25,"is_preprint":false},{"pmid":"25211142","id":"PMC_25211142","title":"SR-BI/CD36 chimeric receptors define extracellular subdomains of SR-BI critical for cholesterol transport.","date":"2014","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25211142","citation_count":25,"is_preprint":false},{"pmid":"34940525","id":"PMC_34940525","title":"Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis.","date":"2021","source":"Journal of cardiovascular development and disease","url":"https://pubmed.ncbi.nlm.nih.gov/34940525","citation_count":23,"is_preprint":false},{"pmid":"22115863","id":"PMC_22115863","title":"ABCA1, ABCG1, and SR-BI: Transit of HDL-associated sphingosine-1-phosphate.","date":"2011","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22115863","citation_count":23,"is_preprint":false},{"pmid":"20629037","id":"PMC_20629037","title":"SR-BI, CD36, and caveolin-1 contribute positively to cholesterol efflux in hepatic cells.","date":"2010","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/20629037","citation_count":23,"is_preprint":false},{"pmid":"30402126","id":"PMC_30402126","title":"Erchen Decoction Ameliorates Lipid Metabolism by the Regulation of the Protein CAV-1 and the Receptors VLDLR, LDLR, ABCA1, and SRB1 in a High-Fat Diet Rat Model.","date":"2018","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/30402126","citation_count":23,"is_preprint":false},{"pmid":"31275377","id":"PMC_31275377","title":"The SR-B1 Receptor as a Potential Target for Treating Glioblastoma.","date":"2019","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31275377","citation_count":22,"is_preprint":false},{"pmid":"30706921","id":"PMC_30706921","title":"DHA and vitamin E antagonized the Aβ25-35-mediated neuron oxidative damage through activation of Nrf2 signaling pathways and regulation of CD36, SRB1 and FABP5 expression in PC12 cells.","date":"2019","source":"Food & function","url":"https://pubmed.ncbi.nlm.nih.gov/30706921","citation_count":21,"is_preprint":false},{"pmid":"32271695","id":"PMC_32271695","title":"CircRNA SCARB1 Promotes Renal Cell Carcinoma Progression Via Mir- 510-5p/SDC3 Axis.","date":"2020","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/32271695","citation_count":21,"is_preprint":false},{"pmid":"18373109","id":"PMC_18373109","title":"NPC1L1 and SR-BI are involved in intestinal cholesterol absorption from small-size lipid donors.","date":"2008","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/18373109","citation_count":21,"is_preprint":false},{"pmid":"21917726","id":"PMC_21917726","title":"C323 of SR-BI is required for SR-BI-mediated HDL binding and cholesteryl ester uptake.","date":"2011","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/21917726","citation_count":21,"is_preprint":false},{"pmid":"31935456","id":"PMC_31935456","title":"SR-BI as a target of natural products and its significance in cancer.","date":"2020","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/31935456","citation_count":20,"is_preprint":false},{"pmid":"26006105","id":"PMC_26006105","title":"Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder.","date":"2015","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26006105","citation_count":20,"is_preprint":false},{"pmid":"30519876","id":"PMC_30519876","title":"Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure.","date":"2018","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/30519876","citation_count":20,"is_preprint":false},{"pmid":"37279381","id":"PMC_37279381","title":"H19 recruited N 6 -methyladenosine (m 6 A) reader YTHDF1 to promote SCARB1 translation and facilitate angiogenesis in gastric cancer.","date":"2023","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/37279381","citation_count":20,"is_preprint":false},{"pmid":"37863040","id":"PMC_37863040","title":"Hepatocytic lipocalin-2 controls HDL metabolism and atherosclerosis via Nedd4-1-SR-BI axis in mice.","date":"2023","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/37863040","citation_count":19,"is_preprint":false},{"pmid":"27225585","id":"PMC_27225585","title":"Shear stress regulates endothelial cell function through SRB1-eNOS signaling pathway.","date":"2016","source":"Cardiovascular therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/27225585","citation_count":19,"is_preprint":false},{"pmid":"9782489","id":"PMC_9782489","title":"Cloning and sequencing of the Candida albicans homologue of SRB1/PSA1/VIG9, the essential gene encoding GDP-mannose pyrophosphorylase in Saccharomyces cerevisiae.","date":"1998","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9782489","citation_count":19,"is_preprint":false},{"pmid":"40684174","id":"PMC_40684174","title":"CircABCA1 promotes ccRCC by reprogramming cholesterol metabolism and facilitating M2 macrophage polarization through IGF2BP3-mediated stabilization of SCARB1 mRNA.","date":"2025","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40684174","citation_count":18,"is_preprint":false},{"pmid":"1525862","id":"PMC_1525862","title":"Complementation of the Saccharomyces cerevisiae srb1-1 mutation: an autoselection system for stable plasmid maintenance.","date":"1992","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1525862","citation_count":18,"is_preprint":false},{"pmid":"29436680","id":"PMC_29436680","title":"Curcumin increases cholesterol efflux via heme oxygenase‑1‑mediated ABCA1 and SR‑BI expression in macrophages.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29436680","citation_count":18,"is_preprint":false},{"pmid":"30103009","id":"PMC_30103009","title":"SCARB1 rs5888 gene polymorphisms in coronary heart disease: A systematic review and a meta-analysis.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30103009","citation_count":17,"is_preprint":false},{"pmid":"34551590","id":"PMC_34551590","title":"Pcpe2, a Novel Extracellular Matrix Protein, Regulates Adipocyte SR-BI-Mediated High-Density Lipoprotein Uptake.","date":"2021","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34551590","citation_count":17,"is_preprint":false},{"pmid":"25993026","id":"PMC_25993026","title":"Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25993026","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49145,"output_tokens":7428,"usd":0.129428,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16819,"output_tokens":6985,"usd":0.12936,"stage2_stop_reason":"end_turn"},"total_usd":0.258788,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"SR-BI (SRB1/CLA-1/CD36L1) was cloned by expression from a CHO cell variant and identified as a new member of the CD36 family of membrane proteins. It binds acetylated LDL, oxidized LDL, and maleylated BSA with high affinity (Kd ~5 µg protein/ml), and unexpectedly also binds native LDL with high affinity, defining a second class (class B) of scavenger receptors.\",\n      \"method\": \"Expression cloning, direct binding and competition assays in CHO cells, Northern blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — expression cloning with direct binding assays, founding paper replicated extensively\",\n      \"pmids\": [\"7520436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SR-BI is an HDL receptor: it binds HDL with high affinity, is expressed primarily in liver and nonplacental steroidogenic tissues, and mediates selective cholesterol uptake (transfer of cholesterol but not HDL outer-shell proteins to cells) by a mechanism distinct from the classic LDL receptor endocytic pathway.\",\n      \"method\": \"HDL binding assays, selective lipid uptake assays in transfected cells, tissue expression analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding and functional uptake assays in transfected cells, replicated extensively across labs\",\n      \"pmids\": [\"8560269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SR-BI (SRB1) recognizes negatively charged liposomes and mediates endocytosis of apoptotic cells; CHO transfectants constitutively expressing SRB1 took up apoptotic cells and negatively charged liposomes, whereas cells expressing class A scavenger receptors (type I or II) could not.\",\n      \"method\": \"Stable CHO cell transfection, endocytosis assays with apoptotic cells and liposomes\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in transfected cells with clear phenotypic readout, single lab\",\n      \"pmids\": [\"8549669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Adenovirus-mediated hepatic overexpression of SR-BI in mice results in virtual disappearance of plasma HDL and a substantial increase in biliary cholesterol, demonstrating that SR-BI directly mediates hepatic HDL cholesterol uptake and increases cholesterol secretion into bile.\",\n      \"method\": \"Adenovirus-mediated gene transfer in mice, plasma HDL measurement, biliary cholesterol quantification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo adenoviral overexpression with quantitative metabolic readouts, replicated across multiple studies\",\n      \"pmids\": [\"9163428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"An alternative splice variant of SR-BI, designated SR-BI.2, differs in its putative cytoplasmic C-terminal domain. CHO cells transfected with SR-BI.2 cDNA expressed protein and acquired the ability to take up fluorescent lipid (DiI) from DiI-HDL, indicating functional selective lipid uptake activity.\",\n      \"method\": \"cDNA cloning, CHO cell transfection, fluorescent DiI-HDL uptake assay, Northern blot\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transfection with functional uptake assay, single lab\",\n      \"pmids\": [\"9254074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Caveolin-1 negatively regulates SR-BI-dependent selective HDL cholesteryl ester uptake. Stable overexpression of caveolin-1 in RAW, J-774, and SR-BI-transfected CHO cells decreased selective HDL [3H]cholesteryl ether uptake by ~50-60% without altering cell-associated HDL. Caveolae depleted of cholesterol (by beta-cyclodextrin) facilitated SR-BI-dependent uptake, while excess cholesterol in caveolae inhibited it.\",\n      \"method\": \"Stable caveolin-1 overexpression, adenoviral gene transfer, [3H]cholesteryl ether selective uptake assay, blocking antibodies, beta-cyclodextrin treatment\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (overexpression, cholesterol depletion, blocking antibodies) in single lab\",\n      \"pmids\": [\"11683884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SR-BI, but not CD36, efficiently directs HDL-derived cholesteryl ester (CE) to a neutral CE hydrolase pathway for hydrolysis at a metabolically active membrane compartment. HDL-CE hydrolytic activity was recovered in a membrane fraction. LDL-CE delivered by SR-BI was also hydrolyzed by neutral CE hydrolase, while CD36-delivered LDL-CE was processed by an acidic CE hydrolase, indicating distinct routing.\",\n      \"method\": \"In vitro CE hydrolysis assays with enzyme inhibitors, subcellular fractionation, comparison of SR-BI and CD36 transfected cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple cell types and inhibitor-based mechanistic dissection, single lab\",\n      \"pmids\": [\"12576515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SR-BI is localized in membrane rafts devoid of caveolin-1 in HepG2 hepatoma cells (demonstrated by detergent-free sucrose gradient fractionation). Both LDL-CE and HDL3-CE selective uptake in HepG2 cells occur via a retroendocytic pathway. Perturbation of membrane raft structure differentially affects LDL-CE vs HDL3-CE selective uptake.\",\n      \"method\": \"Detergent-free sucrose gradient fractionation, cholesterol oxidase/sphingomyelinase/filipin/beta-cyclodextrin treatments, retroendocytosis assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple membrane perturbation methods in single lab with functional readouts\",\n      \"pmids\": [\"15226391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SR-BI is expressed in human intestinal enterocytes from week 14 of gestation, localized mainly over microvilli, and not associated with caveolin-1 or caveolae. Antisense knockdown of SR-BI in Caco-2 cells proportionally decreased free cholesterol uptake (without altering phospholipid or cholesteryl ester capture), and SR-BI antibodies lowered cholesterol uptake in intestinal organ culture.\",\n      \"method\": \"Immunofluorescence, immunogold electron microscopy, antisense transfection in Caco-2 cells, organ culture with blocking antibodies\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific phenotypic readout using multiple approaches, single lab\",\n      \"pmids\": [\"14676281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The adaptor protein PDZK1 binds SR-BI (via its first PDZ domain) and controls hepatic SR-BI expression posttranscriptionally. PDZK1 is phosphorylated at Ser-509 by PKA (cAMP-dependent protein kinase); a S509A mutant PDZK1 lost the ability to upregulate SR-BI protein. Glucagon administration increased PDZK1 phosphorylation at Ser-509 and hepatic SR-BI levels while decreasing plasma HDL.\",\n      \"method\": \"Metabolic labeling, phosphoamino acid analysis, site-directed mutagenesis (S509A), in vitro PKA phosphorylation assay, phospho-specific antibody, in vivo glucagon treatment in rats\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + mutagenesis + in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"16174736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SR-BI-dependent selective cholesterol uptake and HDL resecretion (retroendocytosis) were quantitatively measured in COS-7 and HepG2 cells. The rate of SR-BI-dependent HDL retroendocytosis (~0.5 ng HDL/mg/min) was >30-fold slower than the rate of selective CE uptake (~17 ng HDL/mg/min) in COS-7 cells, demonstrating that the vast majority of SR-BI-dependent selective uptake occurs at the cell surface, not via retroendocytosis.\",\n      \"method\": \"Pulse-chase assay with biotinylated [125I]-HDL3, streptavidin precipitation, quantitative comparison of selective CE uptake vs. retroendocytosis rates\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative biochemical reconstitution approach, single lab\",\n      \"pmids\": [\"16705213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SR-BI is required for normal glucocorticoid synthesis and LPS hepatic clearance. SR-BI-null mice showed glucocorticoid insufficiency due to primary adrenal malfunction from deficient cholesterol delivery from HDL, resulting in uncontrolled inflammatory cytokine response and markedly higher lethality in LPS-induced endotoxic shock. Corticosterone supplementation decreased LPS sensitivity in SR-BI-null mice.\",\n      \"method\": \"SR-BI knockout mice, LPS challenge, corticosterone supplementation rescue, ACTH stimulation tests, hepatocyte LPS clearance assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue experiment and multiple mechanistic readouts\",\n      \"pmids\": [\"18064300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SR-BI binds to the engulfment adaptor protein GULP via its C-terminal intracellular domain (demonstrated by yeast two-hybrid and cell-free binding assay). SR-BI-GULP complex exists prior to activation. Upon PS binding, SR-BI activates GULP, which induces MAPK (p38 and ERK1/2) phosphorylation, which in turn activates Rac1-GTP, leading to actin cytoskeleton rearrangement and phagocytosis of apoptotic cells.\",\n      \"method\": \"Yeast two-hybrid, cell-free binding assay, co-immunoprecipitation, GULP siRNA knockdown, MAPK inhibitor treatment, Rac1-GTP pulldown assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Y2H, co-IP, cell-free binding, loss-of-function, inhibitors) establishing a defined signaling pathway\",\n      \"pmids\": [\"19122200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C323 in the extracellular domain of SR-BI is required for HDL binding and cholesteryl ester uptake. C323G mutant SR-BI lost HDL binding and CE uptake activity. A blocking antibody against the C323 region inhibited HDL binding, directly implicating C323 as part of the HDL binding site. In C323G transgenic mice, plasma cholesterol regulation was impaired. Physiological levels of H2O2 upregulated SR-BI-mediated CE uptake by 65%, while GSH/DTT decreased it by 45%, indicating redox regulation via C323.\",\n      \"method\": \"Site-directed mutagenesis (C323G), blocking antibody, C323G transgenic mice, redox reagent treatment, CE uptake assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis + blocking antibody + transgenic mouse model with multiple functional readouts\",\n      \"pmids\": [\"21917726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SR-BI mediates efferocytosis of apoptotic cells by binding phosphatidylserine and inducing Src phosphorylation and membrane recruitment, leading to downstream activation of PI3K and Rac1 for engulfment. Pharmacological inhibition of Src decreased PI3K, Rac1-GTP, and efferocytosis; Rac1 activation rescued defective efferocytosis in SR-BI−/− macrophages. Bone marrow transplantation showed hematopoietic SR-BI deficiency causes severely defective efferocytosis in atherosclerotic lesions.\",\n      \"method\": \"Bone marrow transplantation, in vitro/in vivo efferocytosis assays, Src/PI3K/Rac1 inhibitors, Rac1-GTP pulldown, SR-BI−/− macrophages\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo bone marrow transplantation + multiple pharmacological pathway dissections + rescue experiments\",\n      \"pmids\": [\"26059978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Macrophage SR-BI regulates LPS-induced pro-inflammatory signaling. Bone marrow transplantation experiments showed SR-BI-null bone marrow enhances inflammatory response to LPS in wild-type recipient mice; WT bone marrow reduces response in SR-BI-null mice. SR-BI overexpression in J774 macrophages attenuated LPS-induced inflammation. The increased signaling in SR-BI-null cells was not related to changes in cellular cholesterol content and involved NFκB, JNK, and p38 pathways.\",\n      \"method\": \"Bone marrow transplantation, SR-BI overexpression in J774 cells, cytokine measurement, signaling pathway inhibitor studies\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal bone marrow transplantation + gain-of-function, single lab\",\n      \"pmids\": [\"22589557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Discrete subdomains of SR-BI's extracellular (EC) domain, particularly in the N-terminal and C-terminal regions, are critical for HDL binding, HDL-CE selective uptake, free cholesterol efflux to HDL, and plasma membrane free cholesterol redistribution. This was shown using a panel of 16 SR-BI/CD36 chimeric receptors; changes in function were independent of receptor oligomerization status.\",\n      \"method\": \"SR-BI/CD36 chimeric receptor panel (16 constructs), transient expression in COS-7 cells, HDL binding assay, CE selective uptake assay, cholesterol efflux assay, plasma membrane cholesterol redistribution assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic domain-swap mutagenesis with multiple functional assays in one rigorous study\",\n      \"pmids\": [\"25211142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SR-B1 is a silica receptor: through an extracellular α-helix, both mouse and human SR-B1 specifically recognize amorphous and crystalline silica (but not other nanoparticles). SR-B1-mediated silica recognition is associated with caspase-1-mediated (canonical) inflammasome activation in macrophages. SR-B1 genetic deletion and masking by monoclonal antibodies showed its requirement for silica-induced pulmonary inflammation in mice.\",\n      \"method\": \"Functional expression cloning, SR-B1 knockout mice, monoclonal antibody blockade, caspase-1 activation assays, murine pulmonary inflammation model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — expression cloning identification + genetic KO + antibody blockade + multiple cell types and in vivo model\",\n      \"pmids\": [\"28147282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SCARB1 mediates cellular carotenoid uptake in birds. Wild-type SCARB1 promotes cellular uptake of carotenoids, but a splice donor site mutation in white recessive canaries causes abnormal splicing (loss of exon 4), producing a predominant isoform that lacks this function. Functional assays confirmed carotenoid uptake activity is lost in the mutant isoform.\",\n      \"method\": \"Genetic mapping, functional carotenoid uptake assays comparing wild-type and mutant SCARB1 isoforms, biochemical analysis of carotenoid tissue levels\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with wild-type vs. mutant isoform comparison + genetic mapping, single study\",\n      \"pmids\": [\"28465440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SR-B1 in endothelial cells mediates LDL transcytosis across the endothelium to promote atherosclerosis. LDL co-localizes with SR-B1 in endothelial intracellular vesicles in vivo. Transcytosis requires direct LDL binding to SR-B1 and an eight-amino-acid cytoplasmic domain that recruits the guanine nucleotide exchange factor DOCK4. DOCK4 promotes SR-B1 internalization and LDL transport by coupling LDL binding to SR-B1 with RAC1 activation.\",\n      \"method\": \"In vivo vesicle co-localization, endothelial monolayer transcytosis assays, cytoplasmic domain deletion mutagenesis, DOCK4 recruitment assays, RAC1 activation assays, SR-B1 endothelial-specific knockout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vivo colocalization, mutagenesis, GEF recruitment, RAC1 assay) in one rigorous study\",\n      \"pmids\": [\"31019307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SR-B1 undergoes multimerization into large metastable clusters at the plasma membrane, which prevents its entry into endocytic pathways and is critical for its function. Multimerization requires the C-terminal leucine zipper of SR-B1 and actin polymerization; mutating the leucine zipper or disrupting actin caused rapid receptor internalization. The C-terminal PDZ-binding domain and cortical cytoskeleton attachment are not responsible for plasmalemmal retention.\",\n      \"method\": \"Single-chain variable fragment (ScFv) antibody-based live-cell imaging, single-molecule tracking, leucine zipper mutagenesis, actin polymerization inhibitors, endocytosis assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — novel live-cell imaging approach + mutagenesis + pharmacological perturbations with clear functional consequence in one rigorous study\",\n      \"pmids\": [\"31231038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Macrophage SR-BI regulates autophagy via TFEB expression and recruitment of the VPS34-Beclin-1 complex. SR-BI deletion reduced PPARα-dependent TFEB expression and VPS34/Beclin-1 levels. Intracellular SR-BI localizes to autophagosomes, where it forms cholesterol domains that recruit Barkor and the VPS34-Beclin-1 complex. Overexpression of TFEB or VPS34 rescued defective autophagy in SR-BI−/− macrophages.\",\n      \"method\": \"SR-BI knockout macrophages, autophagosome fractionation, co-immunoprecipitation of SR-BI with VPS34-Beclin-1 complex, PPARα pathway analysis, TFEB/VPS34 overexpression rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO + subcellular fractionation + co-IP + rescue experiments with multiple orthogonal methods\",\n      \"pmids\": [\"33661763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The splicing factor RBFOX2 maintains a specific Scarb1 isoform profile in mouse liver; decreased RBFOX2 function in diet-induced obesity causes a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. RBFOX2 binding to Scarb1 pre-mRNA was confirmed by enhanced iCLIP. Splice-switching oligonucleotides targeting this network alleviated obesity-induced liver inflammation and promoted an anti-atherogenic lipoprotein profile.\",\n      \"method\": \"Enhanced individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP), diet-induced obesity mouse model, splice-switching oligonucleotides, lipoprotein profiling\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — iCLIP direct binding + in vivo splice-switching rescue + multiple functional readouts\",\n      \"pmids\": [\"36536133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatocyte lipocalin-2 (Lcn2) improves HDL metabolism and alleviates atherosclerosis by blocking Nedd4-1-mediated ubiquitination of SR-BI at K500 and K508. Overexpression of Lcn2 attenuated atherosclerosis via SR-BI; hepatocyte-specific Lcn2 ablation had the opposite effect. Lcn2-improved HDL metabolism was abolished in SR-BI(K500A/K508A) mutation mice and in mice with hepatic SR-BI or Nedd4-1 deletion.\",\n      \"method\": \"Hepatocyte-specific overexpression and knockout mice, ubiquitination site mapping (K500/K508), SR-BI(K500A/K508A) knock-in mice, Nedd4-1 deletion mice, atherosclerosis quantification\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — site-specific ubiquitination mapping + multiple genetic models (KO, KI, conditional KO) with clear functional readouts\",\n      \"pmids\": [\"37863040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal SR-B1 expression is regulated by the FXR pathway. Resveratrol intervention reduces fecal bile acid levels and FXR activity, suppressing jejunal SR-B1 expression via gut microbiome-mediated changes. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1 expression. Intestinal mucosa-specific SR-B1−/− mice on HFD showed improved lipid homeostasis and did not respond further to resveratrol intervention.\",\n      \"method\": \"Intestinal-specific SR-B1 knockout mice, Caco-2 cell treatment, fecal microbiota transplantation, bile acid quantification, FXR pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — intestinal KO + cell-based mechanism + microbiota transplantation, single lab\",\n      \"pmids\": [\"37160898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cigarette smoke causes translocation and loss of SR-B1 from human keratinocytes through H2O2 production (primarily from NADPH oxidase activation). This effect was reversed by NOX inhibitors or catalase pretreatment. CS also caused formation of SR-B1-aldehyde adducts (acrolein and 4-HNE) and increased SR-B1 ubiquitination, contributing to receptor loss.\",\n      \"method\": \"Immunoblotting, immunoprecipitation, RT-PCR, confocal microscopy, NOX inhibitors, catalase pretreatment, aldehyde adduct detection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, confocal, rescue by inhibitors) in single lab\",\n      \"pmids\": [\"22442701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SR-BI-mediated HDL-CE delivery in the adrenal gland occurs at specialized plasma membrane compartments called microvillar channels. Formation of microvillar channels requires SR-BI expression and is regulated by ACTH. SR-BI forms homo-oligomers in the plasma membrane via its C-terminal region (demonstrated by FRET spectroscopy). SR-BI-mediated CE selective uptake is a two-step process: high-affinity HDL binding followed by CE transfer to the membrane.\",\n      \"method\": \"Electron microscopy of adrenal microvillar channels, FRET spectroscopy for oligomerization, ACTH regulation studies, SR-BI expression requirement experiments\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET-based oligomerization assay + electron microscopy localization + ACTH regulation, single lab review compiling primary data\",\n      \"pmids\": [\"18840501\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SR-B1 (SCARB1) is a multispan membrane glycoprotein that functions as the primary HDL receptor, mediating selective uptake of HDL-derived cholesteryl esters into liver and steroidogenic tissues via a non-endocytic, cell-surface mechanism that requires specific extracellular subdomains (including C323) and is modulated by receptor multimerization through a C-terminal leucine zipper; it also facilitates bidirectional free cholesterol flux, LDL transcytosis across endothelium via DOCK4-RAC1 signaling, efferocytosis of apoptotic cells through a GULP-MAPK-Rac1 pathway (or Src-PI3K-Rac1 in macrophages), autophagy regulation via PPARα-TFEB-VPS34/Beclin-1, silica recognition triggering inflammasome activation, and carotenoid uptake; its expression and stability are controlled posttranscriptionally by PDZK1 (regulated by PKA phosphorylation at Ser-509) and by Nedd4-1-mediated ubiquitination at K500/K508 (counteracted by lipocalin-2), while alternative splicing regulated by RBFOX2 and redox modification of C323 further tune its function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCARB1 (SR-BI) is the principal cell-surface HDL receptor, a class B scavenger receptor that mediates selective uptake of HDL-derived cholesteryl esters into liver and steroidogenic tissues by a non-endocytic mechanism distinct from the LDL-receptor pathway [#0, #1]. It binds HDL with high affinity and transfers core lipid to cells without internalizing the lipoprotein particle; in vivo, hepatic SR-BI controls plasma HDL levels and biliary cholesterol secretion [#3], and is required for HDL-dependent cholesterol delivery that sustains adrenal glucocorticoid synthesis [#11]. Selective uptake is a two-step process — high-affinity HDL binding followed by CE transfer — that requires discrete extracellular subdomains including a critical C323 residue subject to redox regulation, with the bulk of CE transfer occurring at the plasma membrane rather than via retroendocytosis [#10, #13, #16, #26]. Surface retention and function depend on receptor multimerization into metastable clusters driven by the C-terminal leucine zipper and actin polymerization, which excludes SR-BI from endocytic pathways [#20]. Receptor abundance and stability are tuned post-transcriptionally: the PDZ adaptor PDZK1 stabilizes hepatic SR-BI in a PKA/Ser-509-dependent manner [#9], Nedd4-1 ubiquitinates SR-BI at K500/K508 to drive its turnover (antagonized by lipocalin-2) [#23], and RBFOX2-controlled alternative splicing sets the hepatic isoform profile governing lipid homeostasis [#22]. Beyond lipoprotein metabolism, SR-BI binds phosphatidylserine to drive efferocytosis of apoptotic cells through GULP–MAPK–Rac1 signaling and a Src–PI3K–Rac1 cascade in macrophages [#12, #14], couples endothelial LDL binding to transcytosis via a cytoplasmic DOCK4–RAC1 module [#19], localizes to autophagosomes to recruit the VPS34–Beclin-1 complex via a PPARα–TFEB axis [#21], and recognizes silica through an extracellular α-helix to trigger inflammasome activation [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established SR-BI as a distinct (class B) scavenger receptor, defining a new receptor class by showing it binds both modified and native LDL with high affinity.\",\n      \"evidence\": \"Expression cloning and direct binding/competition assays in CHO cells\",\n      \"pmids\": [\"7520436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the physiological ligand or the in vivo function\", \"No structural basis for ligand binding\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified SR-BI's physiological role as the HDL receptor mediating selective cholesterol uptake, distinguishing it mechanistically from the endocytic LDL receptor and resolving how cells acquire HDL core lipid.\",\n      \"evidence\": \"HDL binding and selective lipid uptake assays in transfected cells with tissue expression profiling\",\n      \"pmids\": [\"8560269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-surface vs. internalized site of CE transfer not yet resolved\", \"Binding-site residues unmapped\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Extended SR-BI ligand recognition beyond lipoproteins to anionic phospholipid surfaces, linking the receptor to apoptotic cell clearance.\",\n      \"evidence\": \"Gain-of-function endocytosis assays in stable CHO transfectants with apoptotic cells and charged liposomes\",\n      \"pmids\": [\"8549669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream engulfment signaling unknown\", \"Single-lab gain-of-function without genetic validation\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated in vivo that hepatic SR-BI controls plasma HDL and routes cholesterol into bile, establishing its central role in reverse cholesterol transport.\",\n      \"evidence\": \"Adenoviral hepatic overexpression in mice with plasma HDL and biliary cholesterol quantification\",\n      \"pmids\": [\"9163428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression rather than physiological levels\", \"Mechanism of biliary secretion downstream of uptake not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed SR-BI routes HDL-CE to a specific neutral hydrolase compartment distinct from CD36-mediated acidic routing, clarifying the intracellular fate of selectively taken-up lipid.\",\n      \"evidence\": \"In vitro CE hydrolysis assays with inhibitors and subcellular fractionation comparing SR-BI and CD36 transfectants\",\n      \"pmids\": [\"12576515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the hydrolase/compartment not molecularly defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the membrane microenvironment of SR-BI, placing it in caveolin-1-independent rafts and extending its cholesterol-uptake function to intestinal enterocytes.\",\n      \"evidence\": \"Detergent-free fractionation, membrane perturbations, and antisense/antibody loss-of-function in HepG2 and Caco-2/organ culture\",\n      \"pmids\": [\"15226391\", \"14676281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Caveolin-1's regulatory role context-dependent and unresolved across cell types\", \"Tissue-specific uptake mechanisms not unified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined post-transcriptional control of hepatic SR-BI by the PDZK1 adaptor through PKA phosphorylation, linking hormonal (glucagon) signaling to receptor abundance and plasma HDL.\",\n      \"evidence\": \"PKA kinase assays, S509A mutagenesis, phospho-specific antibodies, and in vivo glucagon treatment\",\n      \"pmids\": [\"16174736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which PDZK1 stabilizes SR-BI not detailed\", \"Whether other tissues use this control unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Quantitatively settled that SR-BI-mediated CE uptake occurs predominantly at the cell surface, with retroendocytosis a >30-fold minor route.\",\n      \"evidence\": \"Pulse-chase with biotinylated [125I]-HDL comparing selective uptake and retroendocytosis rates in COS-7 and HepG2 cells\",\n      \"pmids\": [\"16705213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular machinery of surface CE transfer not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the structural and ultrastructural basis of selective uptake — homo-oligomerization via the C-terminus and ACTH-regulated microvillar channels — and a two-step binding/transfer model.\",\n      \"evidence\": \"FRET oligomerization spectroscopy, electron microscopy of adrenal microvillar channels, and ACTH regulation studies\",\n      \"pmids\": [\"18840501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Compiled primary data, single lab\", \"Functional necessity of oligomerization for uptake not isolated here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the physiological consequence of SR-BI-dependent cholesterol delivery to the adrenal, showing it is required for glucocorticoid synthesis and survival of endotoxic challenge.\",\n      \"evidence\": \"SR-BI knockout mice, LPS challenge, corticosterone rescue, and ACTH stimulation tests\",\n      \"pmids\": [\"18064300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SR-BI has direct anti-inflammatory roles independent of cholesterol delivery not separated here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the cytoplasmic GULP–MAPK–Rac1 signaling axis through which SR-BI transduces phosphatidylserine recognition into actin-driven phagocytosis of apoptotic cells.\",\n      \"evidence\": \"Yeast two-hybrid, cell-free binding, co-IP, GULP knockdown, MAPK inhibitors, and Rac1-GTP pulldowns\",\n      \"pmids\": [\"19122200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type generality vs. macrophage-specific pathways not reconciled\", \"In vivo relevance not tested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped C323 in the extracellular domain as part of the HDL binding site and showed CE uptake is redox-regulated through this residue.\",\n      \"evidence\": \"C323G mutagenesis, blocking antibody, transgenic mice, and redox-reagent CE uptake assays\",\n      \"pmids\": [\"21917726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the binding site unresolved\", \"Source/specificity of physiological H2O2 modulation in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined macrophage SR-BI as an in vivo efferocytosis receptor signaling through Src–PI3K–Rac1, demonstrating that hematopoietic SR-BI deficiency impairs apoptotic-cell clearance in atherosclerotic lesions.\",\n      \"evidence\": \"Bone marrow transplantation, efferocytosis assays, Src/PI3K/Rac1 inhibitors, Rac1 rescue, and SR-BI−/− macrophages\",\n      \"pmids\": [\"26059978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between GULP-based and Src-based pathways not unified\", \"Receptor proximal coupling to Src undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed macrophage SR-BI dampens LPS-induced inflammation independent of cellular cholesterol, implicating NF-κB/JNK/p38 signaling.\",\n      \"evidence\": \"Reciprocal bone marrow transplantation and J774 overexpression with cytokine and inhibitor studies\",\n      \"pmids\": [\"22589557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking SR-BI to NF-κB suppression unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated oxidative/electrophilic stress (cigarette smoke H2O2 and aldehyde adducts) drives SR-BI ubiquitination and loss, identifying environmental redox control of receptor stability.\",\n      \"evidence\": \"Immunoblot/IP, confocal microscopy, NOX inhibitors, catalase rescue, and aldehyde adduct detection in keratinocytes\",\n      \"pmids\": [\"22442701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase not identified here\", \"Keratinocyte-specific relevance to lipoprotein metabolism unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Systematically mapped extracellular N- and C-terminal subdomains required for HDL binding, CE uptake, and bidirectional free-cholesterol flux, showing these functions are separable from oligomerization status.\",\n      \"evidence\": \"Panel of 16 SR-BI/CD36 chimeras with binding, uptake, efflux, and membrane cholesterol redistribution assays in COS-7\",\n      \"pmids\": [\"25211142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure to position the subdomains\", \"How separate subdomains coordinate during transfer unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified SR-B1 as a silica receptor recognizing the particle via an extracellular α-helix and required for silica-induced inflammasome activation and pulmonary inflammation.\",\n      \"evidence\": \"Functional expression cloning, SR-B1 knockout mice, antibody blockade, and caspase-1 activation assays\",\n      \"pmids\": [\"28147282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling of surface silica binding to cytosolic inflammasome assembly undefined\", \"Relationship to lipoprotein-binding subdomains unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established SCARB1 as a carotenoid uptake transporter, using a natural splice mutation in canaries to show isoform-dependent loss of carotenoid transport.\",\n      \"evidence\": \"Genetic mapping and carotenoid uptake assays comparing wild-type and exon-4-deficient isoforms\",\n      \"pmids\": [\"28465440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian relevance of carotenoid transport not addressed\", \"Single study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed an endothelial SR-B1 function — LDL transcytosis — driven by a cytoplasmic eight-residue motif recruiting DOCK4 to couple LDL binding to RAC1 activation and internalization, promoting atherosclerosis.\",\n      \"evidence\": \"In vivo vesicle colocalization, transcytosis assays, cytoplasmic deletion mutants, DOCK4 recruitment, RAC1 assays, and endothelial-specific knockout\",\n      \"pmids\": [\"31019307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transcytosis is reconciled with non-endocytic surface retention in other tissues unresolved\", \"Regulation of DOCK4 recruitment unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Explained how SR-B1 avoids endocytosis: it multimerizes into metastable plasma-membrane clusters dependent on the C-terminal leucine zipper and actin, and this clustering is required for function.\",\n      \"evidence\": \"ScFv-based live-cell single-molecule imaging, leucine zipper mutagenesis, actin inhibitors, and endocytosis assays\",\n      \"pmids\": [\"31231038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of functional clusters undefined\", \"How clustering interfaces with transcytosis machinery unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SR-BI to autophagy regulation, showing intracellular SR-BI forms autophagosomal cholesterol domains that recruit the VPS34–Beclin-1 complex via a PPARα–TFEB axis.\",\n      \"evidence\": \"SR-BI knockout macrophages, autophagosome fractionation, co-IP of the VPS34–Beclin-1 complex, and TFEB/VPS34 rescue\",\n      \"pmids\": [\"33661763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SR-BI traffics to autophagosomes unknown\", \"Relationship between surface receptor pool and autophagosomal pool unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified RBFOX2-controlled alternative splicing as a determinant of the hepatic Scarb1 isoform profile governing lipid homeostasis, exploitable with splice-switching oligonucleotides.\",\n      \"evidence\": \"iCLIP demonstrating RBFOX2 binding to Scarb1 pre-mRNA, diet-induced obesity model, and splice-switching oligonucleotide rescue\",\n      \"pmids\": [\"36536133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional differences between the swapped isoforms not fully defined\", \"Human relevance of the isoform switch not established here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a Nedd4-1/lipocalin-2 axis controlling SR-BI degradation, mapping ubiquitination to K500/K508 and showing hepatocyte Lcn2 protects the receptor to improve HDL metabolism and limit atherosclerosis.\",\n      \"evidence\": \"Ubiquitination site mapping, SR-BI(K500A/K508A) knock-in, hepatocyte Lcn2 and Nedd4-1 conditional mice, and atherosclerosis quantification\",\n      \"pmids\": [\"37863040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Lcn2 mechanistically blocks Nedd4-1 access unresolved\", \"Interplay with PDZK1 stabilization not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed intestinal SR-B1 under FXR/bile-acid and microbiome control, linking dietary intervention to receptor expression and systemic lipid homeostasis.\",\n      \"evidence\": \"Intestine-specific SR-B1 knockout mice, Caco-2 CDCA treatment, fecal microbiota transplantation, and FXR pathway analysis\",\n      \"pmids\": [\"37160898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. microbiome-indirect transcriptional control not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and mechanistic model of how SR-BI's extracellular subdomains, clustering state, and divergent cytoplasmic adaptors (PDZK1, DOCK4, GULP, Nedd4-1) are coordinated to switch between surface CE transfer, transcytosis, efferocytosis, and degradation remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of HDL- or silica-bound SR-BI\", \"Rules selecting among competing cytoplasmic effectors unknown\", \"How surface non-endocytic retention coexists with endothelial transcytosis unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 3, 8, 18]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 12, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [12, 14, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 19, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8, 20, 26]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3, 16]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 10, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 14, 15, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 14, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDZK1\", \"GULP1\", \"DOCK4\", \"NEDD4\", \"LCN2\", \"RBFOX2\", \"CAV1\", \"BECN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}