{"gene":"SCARB1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":1995,"finding":"SR-BI (and CD36) are specific cell surface receptors for anionic phospholipids (phosphatidylserine and phosphatidylinositol), demonstrated by direct binding and ligand competition assays in transfected cells; PS liposome binding Kd ~15 µg phospholipid/ml.","method":"Direct binding and ligand competition assays in transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with quantitative Kd, replicated across multiple phospholipid species and receptor variants","pmids":["7541795"],"is_preprint":false},{"year":1996,"finding":"SR-BI (SRB1) recognizes and mediates endocytosis of apoptotic cells as well as negatively charged liposomes, demonstrated in CHO transfectants constitutively expressing SRB1.","method":"CHO cell transfection, uptake assays with apoptotic cells and negatively charged liposomes","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — clean gain-of-function in transfected cells with defined cellular phenotype (endocytosis of apoptotic cells)","pmids":["8549669"],"is_preprint":false},{"year":1998,"finding":"Hepatic SR-BI is the major mediator of selective cholesterol ester (CE) uptake from HDL in vivo; mice with 53% reduced hepatic SR-BI expression showed 47% decrease in selective CE uptake by liver and 53% reduction in selective removal of HDL-CE from plasma, with corresponding 50–70% increase in plasma HDL cholesterol.","method":"Targeted promoter mutation (SR-BI att mice), metabolic studies with nondegradable radiolabeled HDL","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with quantitative metabolic tracing, strong mechanistic evidence","pmids":["9539787"],"is_preprint":false},{"year":2001,"finding":"SR-BI is predominantly associated with caveolae in CHO cells; overexpression of caveolin-1 inhibited SR-BI-dependent selective HDL cholesteryl ester uptake by 50–60% without altering HDL cell association, establishing caveolin-1 as a negative regulator of SR-BI-mediated selective CE uptake.","method":"Stable transfection of caveolin-1 in RAW/J774 cells and SR-BI CHO cells; adenoviral caveolin-1 overexpression; beta-cyclodextrin depletion experiments","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (stable transfection, adenoviral OE, cholesterol depletion) in single study","pmids":["11683884"],"is_preprint":false},{"year":2001,"finding":"SR-BI is required for microvillar channel formation in adrenocortical cells in vivo; SR-BI-null mice lack microvillar channels and have thinner microvillar membranes, demonstrating SR-BI's role in plasma membrane ultrastructure organization.","method":"Electron microscopy comparison of Srb1+/+ and Srb1-/- mouse adrenal glands","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with direct ultrastructural readout","pmids":["11907136"],"is_preprint":false},{"year":2003,"finding":"HDL-associated estradiol stimulates endothelial NO synthase (eNOS) and promotes vasodilation in an SR-BI-dependent manner; this effect was absent in SR-BI null mice and required SR-BI for HDL-mediated estrogen delivery to eNOS.","method":"Ovariectomized and estrogen replacement mouse models; SR-BI null mice; vascular muscle strip relaxation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic KO model with multiple functional readouts (eNOS activation, vasodilation, in vivo models)","pmids":["12750408"],"is_preprint":false},{"year":2003,"finding":"SR-BI and CD36 are receptors for hypochlorite-modified LDL (HOCl-LDL); recognition is mediated by the protein moiety of HOCl-LDL, demonstrated by specific binding to CHO cells overexpressing CD36 and SR-BI and blocking by specific antibodies.","method":"Binding and competition assays in CHO cells overexpressing SR-BI or CD36; blocking antibody experiments; dynamic light scattering","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function transfection with antibody blocking confirming receptor specificity","pmids":["12968020"],"is_preprint":false},{"year":2004,"finding":"SR-BI localizes to membrane rafts devoid of caveolin-1 in HepG2 hepatoma cells; perturbation of membrane raft structure differentially affects LDL-CE and HDL-CE selective uptake; both LDL- and HDL-CE selective uptake occur via a retroendocytic pathway in HepG2 cells.","method":"Detergent-free sucrose gradient fractionation; cholesterol oxidase, sphingomyelinase, filipin, and beta-cyclodextrin treatment; retroendocytosis assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical approaches with functional readouts in single study","pmids":["15226391"],"is_preprint":false},{"year":2005,"finding":"SR-BI mediates vitamin E (alpha- and gamma-tocopherol) intestinal absorption; anti-SR-BI antibodies and BLT-1 (SR-BI inhibitor) blocked up to 80% of vitamin E uptake in Caco-2 cells; SR-BI overexpression in mouse intestine increased gamma-tocopherol bioavailability 2.7-fold.","method":"Caco-2 TC-7 cell monolayer assays with antibody/inhibitor blocking; transgenic mice overexpressing intestinal SR-BI","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vitro blocking and in vivo transgenic mouse model, orthogonal approaches","pmids":["16380385"],"is_preprint":false},{"year":2005,"finding":"PDZK1 is a PDZ-domain adaptor protein that binds to the C-terminal cytoplasmic tail of SR-BI and controls its activity via a tissue-specific posttranscriptional mechanism; PDZK1-deficient mice display near-complete hepatic ablation of SR-BI protein despite normal SR-BI mRNA, resulting in elevated plasma cholesterol.","method":"PDZK1 knockout mice; hepatic SR-BI protein and mRNA analysis","journal":"Current opinion in lipidology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO demonstrates posttranscriptional control of SR-BI by PDZK1 in vivo","pmids":["15767854"],"is_preprint":false},{"year":2006,"finding":"SR-BI-mediated HDL retroendocytosis contributes minimally to selective CE uptake; the vast majority of SR-BI-dependent selective CE uptake occurs at the cell surface in both COS-7 and HepG2 cells, as HDL resecretion rate is >30-fold slower than selective CE uptake rate.","method":"Pulse-chase assay with biotinylated 125I-HDL3; quantitative measurement of HDL uptake and resecretion in SR-BI-expressing cells","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 — quantitative kinetic in vitro assay comparing uptake rates with multiple controls","pmids":["16705213"],"is_preprint":false},{"year":2006,"finding":"Intestinal SR-BI overexpression accelerates absorption of both cholesterol and triglycerides in vivo, demonstrating SR-BI's functional role in intestinal lipid absorption.","method":"Transgenic mice overexpressing SR-BI in intestine; 14C-cholesterol and 3H-triolein absorption assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — transgenic in vivo model with isotopic tracer absorption assays","pmids":["16421100"],"is_preprint":false},{"year":2007,"finding":"Macrophage SR-BI does not contribute to macrophage reverse cholesterol transport in vivo (unlike ABCA1 and ABCG1), demonstrated using SR-BI-deficient primary macrophages in an in vivo RCT assay.","method":"In vivo macrophage RCT assay using SR-BI-deficient primary macrophages transplanted into mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — clean KO macrophages in defined in vivo RCT assay","pmids":["17657311"],"is_preprint":false},{"year":2008,"finding":"SR-BI is required for the antiinflammatory response to LPS-induced endotoxic shock through two mechanisms: (1) facilitating HDL cholesterol delivery to the adrenal gland for glucocorticoid synthesis (primary adrenal malfunction in SR-BI-null mice), and (2) mediating hepatic clearance of LPS.","method":"SR-BI-null mouse model; LPS and ACTH challenge; corticosterone supplementation rescue experiments; LPS plasma clearance assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with pharmacological rescue and mechanistic dissection of two pathways","pmids":["18064300"],"is_preprint":false},{"year":2008,"finding":"SR-BI plays a dual role in Plasmodium liver infection: affecting both sporozoite invasion and intracellular parasite development; RNAi-mediated SR-BI silencing reduced P. berghei and P. falciparum infection in cell lines and in vivo.","method":"RNAi screening in Huh7 cells; SR-BI overexpression; in vivo silencing in mice; SR-BI(+/-) heterozygous mouse model; inhibition of SR-BI in human primary hepatocytes","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (RNAi, OE, genetic mouse model) across species","pmids":["18779053"],"is_preprint":false},{"year":2010,"finding":"PDZK1 interaction with the C-terminal cytoplasmic tail of SR-BI (specifically the final amino acid) is required for SR-BI's role in HCV entry; overexpression of the SR-BI C-terminal cytoplasmic tail (aa 479-509) but not a truncation lacking the last residue competed with PDZK1 and reduced HCV infection.","method":"Stable shRNA knockdown of PDZK1 in Huh-7 cells; GFP-tagged SR-BI C-terminus constructs; Co-IP/interaction assays; HCV infection susceptibility assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — domain mapping with functional rescue experiments and specific deletion constructs","pmids":["20949066"],"is_preprint":false},{"year":2011,"finding":"SR-BI facilitates bidirectional cholesterol flux in macrophages (both efflux and influx from HDL) in non-lipid-loaded cells; SR-BI is present both on the cell surface and intracellularly; HDL CE selective uptake in bone marrow-derived macrophages is not SR-BI-dependent.","method":"Mouse bone marrow-derived macrophage culture; cholesterol efflux and influx assays; SR-BI-null macrophages","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 — single lab with defined cellular assays but limited orthogonal validation","pmids":["21481393"],"is_preprint":false},{"year":2012,"finding":"SR-BI mediates efferocytosis in macrophages via binding phosphatidylserine on apoptotic cells, triggering Src phosphorylation and membrane recruitment, leading to downstream PI3K and Rac1 activation for engulfment; SR-BI deficiency in hematopoietic cells causes severely defective efferocytosis and increased atherosclerotic lesion necrosis.","method":"Bone marrow transplantation in ApoE-/- and LDLR-/- mice; pharmacological inhibition of Src, PI3K, Rac1; SR-BI-/- macrophage efferocytosis assays in vitro and in vivo","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO + pharmacological pathway dissection + in vivo and in vitro readouts, multiple orthogonal approaches","pmids":["26059978"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of LIMP-2 informed homology modeling of SR-BI; mutagenesis of SR-BI revealed a tunnel (cavity) traversing the entire molecule through which cholesterol esters are delivered from bound lipoprotein to the outer leaflet of the plasma membrane, accounting for selective lipid transfer.","method":"Crystal structure of LIMP-2; homology modelling of SR-BI; SR-BI mutagenesis with functional CE uptake assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + homology model + mutagenesis with functional validation in single study","pmids":["24162852"],"is_preprint":false},{"year":2017,"finding":"SR-B1 in endothelial cells mediates LDL transcytosis via direct LDL binding and an eight-amino-acid cytoplasmic domain that recruits the guanine nucleotide exchange factor DOCK4; DOCK4 couples LDL binding to SR-B1 with RAC1 activation for receptor internalization and LDL transport across the endothelium, promoting atherosclerosis.","method":"In vivo mouse studies; LDL co-localization with SR-B1 in endothelial vesicles; domain mutagenesis; DOCK4 interaction (recruitment assays); RAC1 activation assays; endothelial monolayer transcytosis assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in cell-based system, domain mutagenesis, co-localization in vivo, interaction partner identification, pathway confirmation with RAC1","pmids":["31019307"],"is_preprint":false},{"year":2017,"finding":"SR-B1 is a silica receptor; through an extracellular alpha-helix, SR-B1 specifically recognizes amorphous and crystalline silica; SR-B1-mediated silica recognition is associated with caspase-1-mediated inflammasome activation in macrophages and monocytes.","method":"Functional expression cloning; SR-B1 genetic deletion and monoclonal antibody masking; caspase-1 activation assays in mouse macrophages and human PBMCs; in vivo pulmonary inflammation model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — expression cloning identification + KO + antibody blocking + in vivo model, multiple orthogonal approaches","pmids":["28147282"],"is_preprint":false},{"year":2017,"finding":"SCARB1 is required for carotenoid uptake in birds; wild-type SCARB1 promotes cellular uptake of carotenoids, while a mutant isoform lacking exon 4 (due to splice donor site mutation) loses this function, causing absence of carotenoid coloration.","method":"Genetic mapping; biochemical analysis of carotenoids in tissues; functional uptake assays comparing wild-type and mutant SCARB1 isoforms","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — functional assays with wild-type vs. loss-of-function mutant isoform, supported by genetic mapping","pmids":["28465440"],"is_preprint":false},{"year":2017,"finding":"SR-BI mediates HDL transcytosis across brain microvascular endothelial cells in a dynamin-dependent but clathrin-, caveolin-, and PDZK1-independent manner; SR-BI knockdown significantly attenuated HDL internalization, and eNOS inhibition increased HDL internalization.","method":"Spinning-disc confocal and TIRF microscopy; siRNA knockdown of SR-BI, caveolin-1, PDZK1, clathrin heavy chain; pharmacological inhibition of eNOS and NO manipulation","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple siRNA knockdowns + pharmacological inhibitors + live imaging approaches in single study","pmids":["29163190"],"is_preprint":false},{"year":2019,"finding":"SR-B1 undergoes multimerization into large metastable clusters at the plasma membrane through its C-terminal leucine zipper domain; multimerization prevents receptor internalization and is required for plasmalemmal retention and SR-B1 function; disrupting actin polymerization or mutating the leucine zipper impairs multimerization and causes rapid internalization.","method":"Single-chain variable fragment (ScFv) antibody for live-cell imaging; single-molecule tracking; C-terminal domain mutagenesis; actin disruption experiments; sucrose density gradient fractionation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — single-molecule live imaging + domain mutagenesis + multiple functional readouts in single study","pmids":["31231038"],"is_preprint":false},{"year":2019,"finding":"LDL-induced nuclear translocation of endothelial HMGB1 requires SR-BI; endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, which drives SR-BI expression, forming a positive feedback loop.","method":"siRNA knockdown; TIRF microscopy for LDL transcytosis measurement; HMGB1 overexpression; inhibitor studies; SREBP2 half-life measurements; endothelial-specific HMGB1 KO mice with aortic LDL accumulation assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple KD/KO approaches + in vivo genetic model + mechanistic pathway dissection","pmids":["33054399"],"is_preprint":false},{"year":2020,"finding":"Macrophage SR-BI deficiency reduces free cholesterol-induced macrophage apoptosis through upregulation of apoptosis inhibitor of macrophage (AIM); AIM protects SR-BI-deficient macrophages from free cholesterol-induced apoptosis, promoting atherosclerotic plaque growth.","method":"Macrophage-specific SR-BI KO mice (Lysm-Cre x SR-B1f/f); bone marrow transplantation into Ldlr-/- mice; in vitro free cholesterol-induced apoptosis assays; AIM expression analysis","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — conditional KO + bone marrow transplantation + in vitro mechanistic assays","pmids":["31119270"],"is_preprint":false},{"year":2021,"finding":"Macrophage SR-BI regulates autophagy by: (1) enhancing PPARα-dependent TFEB transcription, and (2) localizing to autophagosomes where it forms cholesterol domains and recruits the VPS34-Beclin-1 complex; SR-BI deficiency reduces VPS34 activity and autophagy, increasing foam cell formation and apoptosis.","method":"SR-BI KO macrophages; atherosclerotic aorta analysis; PPARα/TFEB pathway dissection; co-immunoprecipitation of VPS34-Beclin-1 with SR-BI; VPS34 activity assays; Tfeb and Vps34 overexpression rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — KO + co-IP + activity assays + rescue experiments, multiple orthogonal methods","pmids":["33661763"],"is_preprint":false},{"year":2022,"finding":"The RNA splicing factor RBFOX2 regulates Scarb1 alternative splicing in the liver; decreased RBFOX2 function in diet-induced obesity causes a Scarb1 isoform switch that alters hepatocyte lipid homeostasis; splice-switching oligonucleotides targeting this network alleviate obesity-induced liver inflammation.","method":"Enhanced iCLIP of RBFOX2 in mouse liver; RBFOX2 conditional KO; splice-switching oligonucleotides; lipoprotein profiling","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — iCLIP for direct binding + genetic KO + functional oligonucleotide rescue, orthogonal approaches","pmids":["36536133"],"is_preprint":false},{"year":2023,"finding":"Hepatocyte lipocalin-2 (Lcn2) regulates hepatic SR-BI by blocking Nedd4-1-mediated SR-BI ubiquitination at K500 and K508, thereby preventing SR-BI degradation and improving HDL metabolism and alleviating atherogenesis.","method":"Hepatocyte-specific Lcn2 OE and KO mice; Nedd4-1 and SR-BI deletion mice; SR-BI K500A/K508A knock-in mutation mice; ubiquitination assays; HDL metabolic studies","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — site-specific mutagenesis identifying ubiquitination sites + multiple genetic models + in vivo metabolic readouts","pmids":["37863040"],"is_preprint":false},{"year":2023,"finding":"Intestinal FXR activation by bile acids (chenodeoxycholic acid) stimulates SR-B1 expression in enterocytes; resveratrol intervention represses jejunal SR-B1 via gut microbiome-dependent reduction of bile acid levels and FXR activity, thereby inhibiting chylomicron secretion.","method":"Intestinal mucosa-specific SR-B1-/- mice; fecal microbiota transplantation; Caco-2 cell treatment; bile acid quantification; chylomicron secretion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO + FMT + in vitro mechanistic experiments, multiple orthogonal approaches","pmids":["37160898"],"is_preprint":false},{"year":2011,"finding":"SR-BI exhibits negatively cooperative binding of HDL (and LDL); Scatchard and nonlinear least-squares analysis of 125I-HDL binding across an expanded ligand concentration range demonstrated two independent binding site classes or negative cooperativity, ruled out by the infinite dilution dissociation rate method which confirmed negative cooperativity.","method":"Radiolabeled HDL binding assays; Scatchard analysis; infinite dilution dissociation rate method; nonlinear least-squares model fitting","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — rigorous quantitative binding analysis with multiple analytical methods confirming negative cooperativity","pmids":["21254782"],"is_preprint":false},{"year":2012,"finding":"SR-BI null mice exhibit high prevalence of exencephaly in embryos, associated with reduced cholesterol content in SR-BI-/- embryos; SR-BI is expressed in extraembryonic tissues (parietal yolk sac trophoblast cells) and mediates maternal-fetal cholesterol transport required for neural tube closure.","method":"SR-BI-null mouse intercrosses; embryo cholesterol measurement; immunolocalization of SR-BI in extraembryonic tissues; embryonic phenotype analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with biochemical measurement and immunolocalization establishing mechanism","pmids":["23221804"],"is_preprint":false},{"year":2017,"finding":"SR-BI in yolk sac trophoblast giant cells mediates maternal provision of vitamin E to the embryo during neural tube closure; SR-BI-/- embryos have very low vitamin E content; maternal alpha-tocopherol supplementation prevented neural tube defects in SR-BI-/- embryos from 54% to 2%.","method":"SR-BI-/- mouse model; embryonic vitamin E measurement; ROS measurements; dietary supplementation rescue; gene expression analysis (Pax3, Alx1, Alx3)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO model + biochemical measurement + dietary rescue experiment confirming vitamin E transport role","pmids":["28701710"],"is_preprint":false}],"current_model":"SR-B1/SCARB1 is a multiligand membrane receptor that mediates selective bidirectional transport of cholesterol esters and other lipids (including vitamin E and carotenoids) between lipoproteins and cells through a tunnel in its extracellular domain; it forms negatively cooperative, multimeric clusters at the plasma membrane stabilized by a C-terminal leucine zipper and regulated by PDZK1 binding and Nedd4-1-mediated ubiquitination; in endothelial cells it drives LDL transcytosis by recruiting DOCK4 via its cytoplasmic domain to activate RAC1; in macrophages it mediates efferocytosis via PS binding and Src/PI3K/Rac1 signaling and regulates autophagy through PPARα-TFEB and VPS34-Beclin-1 complex recruitment; in steroidogenic and adrenal cells it supplies cholesterol for hormone synthesis; and it also functions as a receptor for anionic phospholipids, apoptotic cells, silica, and as a co-receptor for HCV and Plasmodium entry."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing SR-BI as a specific receptor for anionic phospholipids resolved the question of whether class B scavenger receptors could recognize non-lipoprotein lipid ligands, opening the broader concept of SR-BI as a multiligand receptor.","evidence":"Direct binding and competition assays in transfected cells measuring PS and PI binding with quantitative Kd","pmids":["7541795"],"confidence":"High","gaps":["Physiological relevance of anionic phospholipid binding in vivo not tested","No structural insight into lipid recognition domain"]},{"year":1996,"claim":"Demonstrating that SR-BI mediates endocytosis of apoptotic cells established its role beyond lipid transport as a phagocytic receptor, presaging later efferocytosis studies.","evidence":"Gain-of-function CHO transfection with apoptotic cell and liposome uptake assays","pmids":["8549669"],"confidence":"High","gaps":["Signaling pathway downstream of apoptotic cell recognition unknown","In vivo relevance to atherosclerosis not addressed"]},{"year":1998,"claim":"Quantitative metabolic tracing in SR-BI-attenuated mice proved that hepatic SR-BI is the dominant receptor for selective HDL cholesteryl ester clearance in vivo, establishing its central role in reverse cholesterol transport.","evidence":"SR-BI att mice with 53% reduced expression; nondegradable radiolabeled HDL tracing showing proportional reduction in hepatic CE uptake","pmids":["9539787"],"confidence":"High","gaps":["Structural basis of selective CE uptake unknown","Whether SR-BI mediates whole-particle HDL uptake or only selective lipid transfer not resolved"]},{"year":2001,"claim":"Two studies defined SR-BI's membrane context: caveolin-1 acts as a negative regulator of SR-BI-mediated selective CE uptake, and SR-BI is required for microvillar channel formation in adrenocortical cells, linking receptor function to plasma membrane ultrastructure.","evidence":"Caveolin-1 overexpression in multiple cell lines inhibiting CE uptake; electron microscopy of SR-BI-null adrenal glands lacking microvillar channels","pmids":["11683884","11907136"],"confidence":"High","gaps":["Molecular mechanism by which SR-BI organizes microvillar channels undefined","Whether caveolin-1 regulation occurs in hepatocytes in vivo not established"]},{"year":2003,"claim":"SR-BI was shown to deliver HDL-associated estradiol to endothelial eNOS and to serve as a receptor for hypochlorite-modified LDL, broadening the ligand repertoire beyond native lipoproteins and linking SR-BI to vascular signaling.","evidence":"SR-BI null mice lacking HDL-estradiol-mediated vasodilation; CHO overexpression with antibody blocking confirming HOCl-LDL recognition","pmids":["12750408","12968020"],"confidence":"High","gaps":["Structural determinants of estradiol transfer not identified","Whether oxidized LDL binding uses the same tunnel as CE uptake unknown"]},{"year":2005,"claim":"PDZK1 was identified as a PDZ-domain adaptor essential for hepatic SR-BI protein stability, and SR-BI was shown to mediate intestinal vitamin E and lipid absorption, extending its physiological role to the gut.","evidence":"PDZK1 KO mice with near-complete hepatic SR-BI protein loss despite normal mRNA; Caco-2 blocking and intestinal SR-BI transgenic mice for vitamin E uptake","pmids":["15767854","16380385"],"confidence":"High","gaps":["Mechanism by which PDZK1 prevents SR-BI degradation not resolved","Whether intestinal SR-BI operates via the same selective uptake mechanism as hepatic SR-BI unclear"]},{"year":2006,"claim":"Kinetic studies demonstrated that the vast majority of SR-BI-mediated selective CE uptake occurs at the cell surface rather than via retroendocytosis, refining the mechanistic model of lipid transfer.","evidence":"Pulse-chase assay with biotinylated 125I-HDL3 showing HDL resecretion rate >30-fold slower than selective CE uptake","pmids":["16705213"],"confidence":"High","gaps":["Whether surface-based transfer requires specific membrane domains not fully resolved","Structural basis of surface transfer mechanism unknown at this point"]},{"year":2008,"claim":"SR-BI was linked to innate immunity and infection: it supplies adrenal cholesterol for glucocorticoid synthesis during endotoxemia and clears hepatic LPS, and it serves as a dual host factor for Plasmodium liver invasion and intracellular development.","evidence":"SR-BI null mice with lethal endotoxic shock rescued by corticosterone; RNAi + overexpression + heterozygous mice for Plasmodium infection","pmids":["18064300","18779053"],"confidence":"High","gaps":["Molecular mechanism of LPS clearance by SR-BI not defined","Whether Plasmodium exploits lipid transfer function or a separate binding site unresolved"]},{"year":2011,"claim":"Rigorous binding analysis established that SR-BI exhibits negatively cooperative HDL binding, implying functional receptor oligomerization at the membrane and explaining complex binding kinetics observed in earlier studies.","evidence":"Radiolabeled HDL binding with Scatchard analysis and infinite dilution dissociation rate method confirming negative cooperativity","pmids":["21254782"],"confidence":"High","gaps":["Stoichiometry and structural arrangement of SR-BI oligomers unknown","Whether negative cooperativity extends to all ligand classes not tested"]},{"year":2012,"claim":"SR-BI in extraembryonic tissues was shown to mediate maternal-to-fetal cholesterol and later vitamin E transport required for neural tube closure, establishing a developmental role.","evidence":"SR-BI null embryos with exencephaly and reduced cholesterol; dietary vitamin E supplementation rescuing NTDs from 54% to 2%","pmids":["23221804","28701710"],"confidence":"High","gaps":["Whether SR-BI transports other essential lipids during embryogenesis not examined","Human relevance of this developmental phenotype not established"]},{"year":2013,"claim":"Homology modeling from the LIMP-2 crystal structure combined with SR-BI mutagenesis revealed a hydrophobic tunnel traversing the extracellular domain through which cholesterol esters are transferred from lipoprotein to the plasma membrane, providing the first structural explanation for selective lipid uptake.","evidence":"LIMP-2 crystal structure; SR-BI homology model; tunnel-disrupting mutations abolishing CE uptake","pmids":["24162852"],"confidence":"High","gaps":["No direct SR-BI crystal structure available","Dynamics of lipid transit through the tunnel not characterized","Whether all lipid ligands use the same tunnel unresolved"]},{"year":2015,"claim":"Mechanistic dissection of macrophage efferocytosis showed that SR-BI binds phosphatidylserine on apoptotic cells and signals through Src→PI3K→Rac1 to drive engulfment, with SR-BI hematopoietic deficiency causing increased atherosclerotic necrosis in vivo.","evidence":"SR-BI KO macrophages with pharmacological Src/PI3K/Rac1 inhibition; bone marrow transplantation in ApoE−/− and LDLR−/− mice","pmids":["26059978"],"confidence":"High","gaps":["Whether SR-BI efferocytosis and lipid uptake functions are structurally separable unknown","Identity of co-receptors in efferocytosis signaling not defined"]},{"year":2017,"claim":"Multiple discoveries in 2017 revealed that endothelial SR-BI drives LDL transcytosis via DOCK4/RAC1 recruitment to its cytoplasmic tail promoting atherosclerosis, that SR-BI recognizes silica through an extracellular α-helix triggering inflammasome activation, and that SR-BI mediates carotenoid uptake and dynamin-dependent HDL transcytosis across brain endothelium.","evidence":"Domain mutagenesis and DOCK4 interaction in endothelial monolayers; expression cloning and SR-BI KO for silica recognition; functional assays with WT vs. exon-4-deleted SCARB1 for carotenoid uptake; siRNA and pharmacological inhibitor panel for brain endothelial HDL transcytosis","pmids":["31019307","28147282","28465440","29163190"],"confidence":"High","gaps":["Whether DOCK4-dependent transcytosis pathway operates in brain endothelium not tested","Crystal structure of SR-BI silica-binding helix not determined","Mechanism of carotenoid transfer through the tunnel not characterized"]},{"year":2019,"claim":"Single-molecule imaging revealed that SR-BI forms large metastable clusters at the plasma membrane via a C-terminal leucine zipper, and that multimerization prevents internalization and is essential for receptor function, unifying earlier observations of negative cooperativity and surface-based lipid transfer.","evidence":"Single-chain antibody live-cell imaging; single-molecule tracking; leucine zipper mutagenesis causing rapid internalization","pmids":["31231038"],"confidence":"High","gaps":["Precise oligomeric stoichiometry not determined","How PDZK1 binding interfaces with cluster formation not resolved"]},{"year":2019,"claim":"HMGB1 nuclear translocation triggered by LDL requires SR-BI in endothelial cells, creating a positive feedback loop where HMGB1 stabilizes SREBP2 to increase SR-BI expression and sustain LDL transcytosis.","evidence":"siRNA knockdown, TIRF microscopy, endothelial HMGB1 KO mice with aortic LDL accumulation measurements","pmids":["33054399"],"confidence":"High","gaps":["Whether this feedback loop operates in non-endothelial cells unknown","Direct physical interaction between HMGB1 and SR-BI not demonstrated"]},{"year":2021,"claim":"SR-BI was discovered to regulate macrophage autophagy through two mechanisms—PPARα-dependent TFEB transcription and direct recruitment of VPS34–Beclin-1 to autophagosomal cholesterol domains—explaining how SR-BI deficiency promotes foam cell formation and apoptosis.","evidence":"SR-BI KO macrophages; co-IP of VPS34–Beclin-1; VPS34 activity assays; Tfeb and Vps34 overexpression rescue","pmids":["33661763"],"confidence":"High","gaps":["Whether autophagy regulation is specific to macrophages or general unknown","How SR-BI cholesterol domains are organized on autophagosomes not structurally resolved"]},{"year":2022,"claim":"RBFOX2-dependent alternative splicing of Scarb1 in the liver was identified as a regulatory layer altered in obesity, with splice-switching oligonucleotides rescuing hepatic lipid homeostasis, revealing a post-transcriptional control axis distinct from PDZK1-mediated protein stabilization.","evidence":"Enhanced iCLIP of RBFOX2 in mouse liver; RBFOX2 conditional KO; splice-switching oligonucleotides correcting Scarb1 isoform ratio","pmids":["36536133"],"confidence":"High","gaps":["Functional difference between Scarb1 splice isoforms not fully characterized","Whether RBFOX2-mediated splicing is conserved in human liver not confirmed"]},{"year":2023,"claim":"Two studies refined SR-BI regulation: Nedd4-1 ubiquitinates SR-BI at K500/K508 to promote its degradation (counteracted by lipocalin-2), and intestinal FXR–bile acid signaling drives SR-BI expression in enterocytes to regulate chylomicron secretion.","evidence":"K500A/K508A knock-in mice and hepatocyte Lcn2 KO/OE for ubiquitination; intestinal SR-BI KO and FMT with bile acid quantification for FXR regulation","pmids":["37863040","37160898"],"confidence":"High","gaps":["Whether other E3 ligases also target SR-BI unresolved","How ubiquitination at K500/K508 interfaces with leucine zipper-mediated clustering unknown","Whether FXR-driven intestinal SR-BI regulation affects systemic vitamin E status not tested"]},{"year":null,"claim":"A high-resolution crystal or cryo-EM structure of SR-BI itself—rather than a LIMP-2-based homology model—is needed to define the lipid tunnel geometry, explain ligand selectivity, and map the silica-binding and PS-binding interfaces.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimental SR-BI structure available","Structural basis of negative cooperativity and leucine zipper-mediated clustering unresolved","Whether the DOCK4-binding cytoplasmic motif and PDZK1-binding C-terminus create allosteric cross-talk is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,8,11,19,21]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,2,7,18]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,8,18,31,32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,4,23,30]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[16,19,22]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,8,11,18,29]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,7,8,11,27,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,17,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,15]}],"complexes":[],"partners":["PDZK1","DOCK4","RAC1","NEDD4","VPS34","BECN1","CAV1","RBFOX2"],"other_free_text":[]},"mechanistic_narrative":"SCARB1 encodes SR-BI, a multiligand cell-surface scavenger receptor that mediates selective, bidirectional transfer of cholesterol esters, vitamin E, and carotenoids between lipoproteins and cells through a hydrophobic tunnel traversing its extracellular domain [PMID:24162852, PMID:9539787, PMID:16380385, PMID:28465440]. In the liver, SR-BI is the principal receptor for selective HDL cholesteryl ester uptake, with its surface abundance controlled by PDZK1-dependent posttranscriptional stabilization, Nedd4-1-mediated ubiquitination at K500/K508, RBFOX2-regulated alternative splicing, and assembly into negatively cooperative, leucine-zipper-stabilized plasma membrane clusters [PMID:15767854, PMID:37863040, PMID:36536133, PMID:31231038, PMID:21254782]. In endothelial cells SR-BI drives LDL transcytosis by recruiting DOCK4 via an eight-amino-acid cytoplasmic motif to activate RAC1, while in macrophages it mediates efferocytosis through phosphatidylserine binding and Src/PI3K/Rac1 signaling and regulates autophagy via PPARα–TFEB transcription and VPS34–Beclin-1 complex recruitment [PMID:31019307, PMID:26059978, PMID:33661763]. SR-BI also functions as a host entry factor for HCV and Plasmodium sporozoites and as a receptor for silica particles that triggers inflammasome activation [PMID:20949066, PMID:18779053, PMID:28147282]."},"prefetch_data":{"uniprot":{"accession":"Q8WTV0","full_name":"Scavenger receptor class B member 1","aliases":["CD36 and LIMPII analogous 1","CLA-1","CD36 antigen-like 1","Collagen type I receptor, thrombospondin receptor-like 1","SR-BI"],"length_aa":552,"mass_kda":60.9,"function":"Receptor for different ligands such as phospholipids, cholesterol ester, lipoproteins, phosphatidylserine and apoptotic cells (PubMed:12016218, PubMed:12519372, PubMed:21226579). Receptor for HDL, mediating selective uptake of cholesteryl ether and HDL-dependent cholesterol efflux (PubMed:26965621). Also facilitates the flux of free and esterified cholesterol between the cell surface and apoB-containing lipoproteins and modified lipoproteins, although less efficiently than HDL. May be involved in the phagocytosis of apoptotic cells, via its phosphatidylserine binding activity (PubMed:12016218) (Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes and appears to facilitate its cell entry (PubMed:12356718, PubMed:12913001, PubMed:18000990). Binding between SCARB1 and the hepatitis C virus glycoprotein E2 is independent of the genotype of the viral isolate (PubMed:12356718) (Microbial infection) Mediates uptake of M.fortuitum, E.coli and S.aureus (Microbial infection) Facilitates the entry of human coronavirus SARS-CoV-2 by acting as an entry cofactor through HDL binding","subcellular_location":"Cell membrane; Membrane, caveola","url":"https://www.uniprot.org/uniprotkb/Q8WTV0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCARB1","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SCARB1","total_profiled":1310},"omim":[{"mim_id":"620410","title":"LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 3; LDLCQ3","url":"https://www.omim.org/entry/620410"},{"mim_id":"617966","title":"LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 7; LDLCQ7","url":"https://www.omim.org/entry/617966"},{"mim_id":"615576","title":"MICRO RNA 185; MIR185","url":"https://www.omim.org/entry/615576"},{"mim_id":"612019","title":"INTESTINE-SPECIFIC HOMEOBOX; ISX","url":"https://www.omim.org/entry/612019"},{"mim_id":"611740","title":"BETA-CAROTENE OXYGENASE 2; BCO2","url":"https://www.omim.org/entry/611740"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Lysosomes","reliability":"Additional"},{"location":"Rods & Rings","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":235.6},{"tissue":"liver","ntpm":66.0},{"tissue":"placenta","ntpm":104.6}],"url":"https://www.proteinatlas.org/search/SCARB1"},"hgnc":{"alias_symbol":["SRB1","CLA-1","CLA1","SR-BI"],"prev_symbol":["CD36L1"]},"alphafold":{"accession":"Q8WTV0","domains":[{"cath_id":"-","chopping":"63-423","consensus_level":"medium","plddt":93.9117,"start":63,"end":423},{"cath_id":"1.10.287","chopping":"15-51_437-465","consensus_level":"medium","plddt":88.7145,"start":15,"end":465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WTV0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WTV0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WTV0-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCARB1","jax_strain_url":"https://www.jax.org/strain/search?query=SCARB1"},"sequence":{"accession":"Q8WTV0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WTV0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WTV0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WTV0"}},"corpus_meta":[{"pmid":"7541795","id":"PMC_7541795","title":"The 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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":"31467425","id":"PMC_31467425","title":"The high-density lipoprotein receptor Scarb1 is required for normal bone differentiation in vivo and in vitro.","date":"2019","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31467425","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":"25281615","id":"PMC_25281615","title":"Scavenger receptor class B, type I (Scarb1) deficiency promotes osteoblastogenesis but stunts terminal osteocyte differentiation.","date":"2014","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/25281615","citation_count":20,"is_preprint":false},{"pmid":"21254782","id":"PMC_21254782","title":"Negatively cooperative binding of high-density lipoprotein to the HDL receptor SR-BI.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21254782","citation_count":20,"is_preprint":false},{"pmid":"17533223","id":"PMC_17533223","title":"Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI.","date":"2007","source":"Journal of lipid 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journal","url":"https://pubmed.ncbi.nlm.nih.gov/37279381","citation_count":19,"is_preprint":false},{"pmid":"28701710","id":"PMC_28701710","title":"Deficient Vitamin E Uptake During Development Impairs Neural Tube Closure in Mice Lacking Lipoprotein Receptor SR-BI.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28701710","citation_count":19,"is_preprint":false},{"pmid":"17311943","id":"PMC_17311943","title":"Scavenger receptor class B type I (SCARB1) c.1119C>T polymorphism affects postprandial triglyceride metabolism in men.","date":"2007","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/17311943","citation_count":19,"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 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endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24928939","citation_count":16,"is_preprint":false},{"pmid":"28105139","id":"PMC_28105139","title":"Baicalin promotes cholesterol efflux by regulating the expression of SR-BI in macrophages.","date":"2016","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28105139","citation_count":16,"is_preprint":false},{"pmid":"27377933","id":"PMC_27377933","title":"ApoA-I induces S1P release from endothelial cells through ABCA1 and SR-BI in a positive feedback manner.","date":"2016","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27377933","citation_count":16,"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":15,"is_preprint":false},{"pmid":"30823658","id":"PMC_30823658","title":"Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30823658","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50927,"output_tokens":7613,"usd":0.133488},"stage2":{"model":"claude-opus-4-6","input_tokens":11357,"output_tokens":4661,"usd":0.259965},"total_usd":0.393453,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"SR-BI (and CD36) are specific cell surface receptors for anionic phospholipids (phosphatidylserine and phosphatidylinositol), demonstrated by direct binding and ligand competition assays in transfected cells; PS liposome binding Kd ~15 µg phospholipid/ml.\",\n      \"method\": \"Direct binding and ligand competition assays in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with quantitative Kd, replicated across multiple phospholipid species and receptor variants\",\n      \"pmids\": [\"7541795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SR-BI (SRB1) recognizes and mediates endocytosis of apoptotic cells as well as negatively charged liposomes, demonstrated in CHO transfectants constitutively expressing SRB1.\",\n      \"method\": \"CHO cell transfection, uptake assays with apoptotic cells and negatively charged liposomes\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function in transfected cells with defined cellular phenotype (endocytosis of apoptotic cells)\",\n      \"pmids\": [\"8549669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Hepatic SR-BI is the major mediator of selective cholesterol ester (CE) uptake from HDL in vivo; mice with 53% reduced hepatic SR-BI expression showed 47% decrease in selective CE uptake by liver and 53% reduction in selective removal of HDL-CE from plasma, with corresponding 50–70% increase in plasma HDL cholesterol.\",\n      \"method\": \"Targeted promoter mutation (SR-BI att mice), metabolic studies with nondegradable radiolabeled HDL\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with quantitative metabolic tracing, strong mechanistic evidence\",\n      \"pmids\": [\"9539787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SR-BI is predominantly associated with caveolae in CHO cells; overexpression of caveolin-1 inhibited SR-BI-dependent selective HDL cholesteryl ester uptake by 50–60% without altering HDL cell association, establishing caveolin-1 as a negative regulator of SR-BI-mediated selective CE uptake.\",\n      \"method\": \"Stable transfection of caveolin-1 in RAW/J774 cells and SR-BI CHO cells; adenoviral caveolin-1 overexpression; beta-cyclodextrin depletion experiments\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (stable transfection, adenoviral OE, cholesterol depletion) in single study\",\n      \"pmids\": [\"11683884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SR-BI is required for microvillar channel formation in adrenocortical cells in vivo; SR-BI-null mice lack microvillar channels and have thinner microvillar membranes, demonstrating SR-BI's role in plasma membrane ultrastructure organization.\",\n      \"method\": \"Electron microscopy comparison of Srb1+/+ and Srb1-/- mouse adrenal glands\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with direct ultrastructural readout\",\n      \"pmids\": [\"11907136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HDL-associated estradiol stimulates endothelial NO synthase (eNOS) and promotes vasodilation in an SR-BI-dependent manner; this effect was absent in SR-BI null mice and required SR-BI for HDL-mediated estrogen delivery to eNOS.\",\n      \"method\": \"Ovariectomized and estrogen replacement mouse models; SR-BI null mice; vascular muscle strip relaxation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO model with multiple functional readouts (eNOS activation, vasodilation, in vivo models)\",\n      \"pmids\": [\"12750408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SR-BI and CD36 are receptors for hypochlorite-modified LDL (HOCl-LDL); recognition is mediated by the protein moiety of HOCl-LDL, demonstrated by specific binding to CHO cells overexpressing CD36 and SR-BI and blocking by specific antibodies.\",\n      \"method\": \"Binding and competition assays in CHO cells overexpressing SR-BI or CD36; blocking antibody experiments; dynamic light scattering\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function transfection with antibody blocking confirming receptor specificity\",\n      \"pmids\": [\"12968020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SR-BI localizes to membrane rafts devoid of caveolin-1 in HepG2 hepatoma cells; perturbation of membrane raft structure differentially affects LDL-CE and HDL-CE selective uptake; both LDL- and HDL-CE selective uptake occur via a retroendocytic pathway in HepG2 cells.\",\n      \"method\": \"Detergent-free sucrose gradient fractionation; cholesterol oxidase, sphingomyelinase, filipin, and beta-cyclodextrin treatment; retroendocytosis assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical approaches with functional readouts in single study\",\n      \"pmids\": [\"15226391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SR-BI mediates vitamin E (alpha- and gamma-tocopherol) intestinal absorption; anti-SR-BI antibodies and BLT-1 (SR-BI inhibitor) blocked up to 80% of vitamin E uptake in Caco-2 cells; SR-BI overexpression in mouse intestine increased gamma-tocopherol bioavailability 2.7-fold.\",\n      \"method\": \"Caco-2 TC-7 cell monolayer assays with antibody/inhibitor blocking; transgenic mice overexpressing intestinal SR-BI\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro blocking and in vivo transgenic mouse model, orthogonal approaches\",\n      \"pmids\": [\"16380385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PDZK1 is a PDZ-domain adaptor protein that binds to the C-terminal cytoplasmic tail of SR-BI and controls its activity via a tissue-specific posttranscriptional mechanism; PDZK1-deficient mice display near-complete hepatic ablation of SR-BI protein despite normal SR-BI mRNA, resulting in elevated plasma cholesterol.\",\n      \"method\": \"PDZK1 knockout mice; hepatic SR-BI protein and mRNA analysis\",\n      \"journal\": \"Current opinion in lipidology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO demonstrates posttranscriptional control of SR-BI by PDZK1 in vivo\",\n      \"pmids\": [\"15767854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SR-BI-mediated HDL retroendocytosis contributes minimally to selective CE uptake; the vast majority of SR-BI-dependent selective CE uptake occurs at the cell surface in both COS-7 and HepG2 cells, as HDL resecretion rate is >30-fold slower than selective CE uptake rate.\",\n      \"method\": \"Pulse-chase assay with biotinylated 125I-HDL3; quantitative measurement of HDL uptake and resecretion in SR-BI-expressing cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative kinetic in vitro assay comparing uptake rates with multiple controls\",\n      \"pmids\": [\"16705213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Intestinal SR-BI overexpression accelerates absorption of both cholesterol and triglycerides in vivo, demonstrating SR-BI's functional role in intestinal lipid absorption.\",\n      \"method\": \"Transgenic mice overexpressing SR-BI in intestine; 14C-cholesterol and 3H-triolein absorption assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic in vivo model with isotopic tracer absorption assays\",\n      \"pmids\": [\"16421100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Macrophage SR-BI does not contribute to macrophage reverse cholesterol transport in vivo (unlike ABCA1 and ABCG1), demonstrated using SR-BI-deficient primary macrophages in an in vivo RCT assay.\",\n      \"method\": \"In vivo macrophage RCT assay using SR-BI-deficient primary macrophages transplanted into mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO macrophages in defined in vivo RCT assay\",\n      \"pmids\": [\"17657311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SR-BI is required for the antiinflammatory response to LPS-induced endotoxic shock through two mechanisms: (1) facilitating HDL cholesterol delivery to the adrenal gland for glucocorticoid synthesis (primary adrenal malfunction in SR-BI-null mice), and (2) mediating hepatic clearance of LPS.\",\n      \"method\": \"SR-BI-null mouse model; LPS and ACTH challenge; corticosterone supplementation rescue experiments; LPS plasma clearance assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with pharmacological rescue and mechanistic dissection of two pathways\",\n      \"pmids\": [\"18064300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SR-BI plays a dual role in Plasmodium liver infection: affecting both sporozoite invasion and intracellular parasite development; RNAi-mediated SR-BI silencing reduced P. berghei and P. falciparum infection in cell lines and in vivo.\",\n      \"method\": \"RNAi screening in Huh7 cells; SR-BI overexpression; in vivo silencing in mice; SR-BI(+/-) heterozygous mouse model; inhibition of SR-BI in human primary hepatocytes\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (RNAi, OE, genetic mouse model) across species\",\n      \"pmids\": [\"18779053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDZK1 interaction with the C-terminal cytoplasmic tail of SR-BI (specifically the final amino acid) is required for SR-BI's role in HCV entry; overexpression of the SR-BI C-terminal cytoplasmic tail (aa 479-509) but not a truncation lacking the last residue competed with PDZK1 and reduced HCV infection.\",\n      \"method\": \"Stable shRNA knockdown of PDZK1 in Huh-7 cells; GFP-tagged SR-BI C-terminus constructs; Co-IP/interaction assays; HCV infection susceptibility assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional rescue experiments and specific deletion constructs\",\n      \"pmids\": [\"20949066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SR-BI facilitates bidirectional cholesterol flux in macrophages (both efflux and influx from HDL) in non-lipid-loaded cells; SR-BI is present both on the cell surface and intracellularly; HDL CE selective uptake in bone marrow-derived macrophages is not SR-BI-dependent.\",\n      \"method\": \"Mouse bone marrow-derived macrophage culture; cholesterol efflux and influx assays; SR-BI-null macrophages\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single lab with defined cellular assays but limited orthogonal validation\",\n      \"pmids\": [\"21481393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SR-BI mediates efferocytosis in macrophages via binding phosphatidylserine on apoptotic cells, triggering Src phosphorylation and membrane recruitment, leading to downstream PI3K and Rac1 activation for engulfment; SR-BI deficiency in hematopoietic cells causes severely defective efferocytosis and increased atherosclerotic lesion necrosis.\",\n      \"method\": \"Bone marrow transplantation in ApoE-/- and LDLR-/- mice; pharmacological inhibition of Src, PI3K, Rac1; SR-BI-/- macrophage efferocytosis assays in vitro and in vivo\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + pharmacological pathway dissection + in vivo and in vitro readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"26059978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of LIMP-2 informed homology modeling of SR-BI; mutagenesis of SR-BI revealed a tunnel (cavity) traversing the entire molecule through which cholesterol esters are delivered from bound lipoprotein to the outer leaflet of the plasma membrane, accounting for selective lipid transfer.\",\n      \"method\": \"Crystal structure of LIMP-2; homology modelling of SR-BI; SR-BI mutagenesis with functional CE uptake assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + homology model + mutagenesis with functional validation in single study\",\n      \"pmids\": [\"24162852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SR-B1 in endothelial cells mediates LDL transcytosis via direct LDL binding and an eight-amino-acid cytoplasmic domain that recruits the guanine nucleotide exchange factor DOCK4; DOCK4 couples LDL binding to SR-B1 with RAC1 activation for receptor internalization and LDL transport across the endothelium, promoting atherosclerosis.\",\n      \"method\": \"In vivo mouse studies; LDL co-localization with SR-B1 in endothelial vesicles; domain mutagenesis; DOCK4 interaction (recruitment assays); RAC1 activation assays; endothelial monolayer transcytosis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in cell-based system, domain mutagenesis, co-localization in vivo, interaction partner identification, pathway confirmation with RAC1\",\n      \"pmids\": [\"31019307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SR-B1 is a silica receptor; through an extracellular alpha-helix, SR-B1 specifically recognizes amorphous and crystalline silica; SR-B1-mediated silica recognition is associated with caspase-1-mediated inflammasome activation in macrophages and monocytes.\",\n      \"method\": \"Functional expression cloning; SR-B1 genetic deletion and monoclonal antibody masking; caspase-1 activation assays in mouse macrophages and human PBMCs; in vivo pulmonary inflammation model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — expression cloning identification + KO + antibody blocking + in vivo model, multiple orthogonal approaches\",\n      \"pmids\": [\"28147282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SCARB1 is required for carotenoid uptake in birds; wild-type SCARB1 promotes cellular uptake of carotenoids, while a mutant isoform lacking exon 4 (due to splice donor site mutation) loses this function, causing absence of carotenoid coloration.\",\n      \"method\": \"Genetic mapping; biochemical analysis of carotenoids in tissues; functional uptake assays comparing wild-type and mutant SCARB1 isoforms\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with wild-type vs. loss-of-function mutant isoform, supported by genetic mapping\",\n      \"pmids\": [\"28465440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SR-BI mediates HDL transcytosis across brain microvascular endothelial cells in a dynamin-dependent but clathrin-, caveolin-, and PDZK1-independent manner; SR-BI knockdown significantly attenuated HDL internalization, and eNOS inhibition increased HDL internalization.\",\n      \"method\": \"Spinning-disc confocal and TIRF microscopy; siRNA knockdown of SR-BI, caveolin-1, PDZK1, clathrin heavy chain; pharmacological inhibition of eNOS and NO manipulation\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple siRNA knockdowns + pharmacological inhibitors + live imaging approaches in single study\",\n      \"pmids\": [\"29163190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SR-B1 undergoes multimerization into large metastable clusters at the plasma membrane through its C-terminal leucine zipper domain; multimerization prevents receptor internalization and is required for plasmalemmal retention and SR-B1 function; disrupting actin polymerization or mutating the leucine zipper impairs multimerization and causes rapid internalization.\",\n      \"method\": \"Single-chain variable fragment (ScFv) antibody for live-cell imaging; single-molecule tracking; C-terminal domain mutagenesis; actin disruption experiments; sucrose density gradient fractionation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — single-molecule live imaging + domain mutagenesis + multiple functional readouts in single study\",\n      \"pmids\": [\"31231038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDL-induced nuclear translocation of endothelial HMGB1 requires SR-BI; endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, which drives SR-BI expression, forming a positive feedback loop.\",\n      \"method\": \"siRNA knockdown; TIRF microscopy for LDL transcytosis measurement; HMGB1 overexpression; inhibitor studies; SREBP2 half-life measurements; endothelial-specific HMGB1 KO mice with aortic LDL accumulation assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KD/KO approaches + in vivo genetic model + mechanistic pathway dissection\",\n      \"pmids\": [\"33054399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Macrophage SR-BI deficiency reduces free cholesterol-induced macrophage apoptosis through upregulation of apoptosis inhibitor of macrophage (AIM); AIM protects SR-BI-deficient macrophages from free cholesterol-induced apoptosis, promoting atherosclerotic plaque growth.\",\n      \"method\": \"Macrophage-specific SR-BI KO mice (Lysm-Cre x SR-B1f/f); bone marrow transplantation into Ldlr-/- mice; in vitro free cholesterol-induced apoptosis assays; AIM expression analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO + bone marrow transplantation + in vitro mechanistic assays\",\n      \"pmids\": [\"31119270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Macrophage SR-BI regulates autophagy by: (1) enhancing PPARα-dependent TFEB transcription, and (2) localizing to autophagosomes where it forms cholesterol domains and recruits the VPS34-Beclin-1 complex; SR-BI deficiency reduces VPS34 activity and autophagy, increasing foam cell formation and apoptosis.\",\n      \"method\": \"SR-BI KO macrophages; atherosclerotic aorta analysis; PPARα/TFEB pathway dissection; co-immunoprecipitation of VPS34-Beclin-1 with SR-BI; VPS34 activity assays; Tfeb and Vps34 overexpression rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO + co-IP + activity assays + rescue experiments, multiple orthogonal methods\",\n      \"pmids\": [\"33661763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The RNA splicing factor RBFOX2 regulates Scarb1 alternative splicing in the liver; decreased RBFOX2 function in diet-induced obesity causes a Scarb1 isoform switch that alters hepatocyte lipid homeostasis; splice-switching oligonucleotides targeting this network alleviate obesity-induced liver inflammation.\",\n      \"method\": \"Enhanced iCLIP of RBFOX2 in mouse liver; RBFOX2 conditional KO; splice-switching oligonucleotides; lipoprotein profiling\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — iCLIP for direct binding + genetic KO + functional oligonucleotide rescue, orthogonal approaches\",\n      \"pmids\": [\"36536133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatocyte lipocalin-2 (Lcn2) regulates hepatic SR-BI by blocking Nedd4-1-mediated SR-BI ubiquitination at K500 and K508, thereby preventing SR-BI degradation and improving HDL metabolism and alleviating atherogenesis.\",\n      \"method\": \"Hepatocyte-specific Lcn2 OE and KO mice; Nedd4-1 and SR-BI deletion mice; SR-BI K500A/K508A knock-in mutation mice; ubiquitination assays; HDL metabolic studies\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-specific mutagenesis identifying ubiquitination sites + multiple genetic models + in vivo metabolic readouts\",\n      \"pmids\": [\"37863040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal FXR activation by bile acids (chenodeoxycholic acid) stimulates SR-B1 expression in enterocytes; resveratrol intervention represses jejunal SR-B1 via gut microbiome-dependent reduction of bile acid levels and FXR activity, thereby inhibiting chylomicron secretion.\",\n      \"method\": \"Intestinal mucosa-specific SR-B1-/- mice; fecal microbiota transplantation; Caco-2 cell treatment; bile acid quantification; chylomicron secretion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO + FMT + in vitro mechanistic experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"37160898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SR-BI exhibits negatively cooperative binding of HDL (and LDL); Scatchard and nonlinear least-squares analysis of 125I-HDL binding across an expanded ligand concentration range demonstrated two independent binding site classes or negative cooperativity, ruled out by the infinite dilution dissociation rate method which confirmed negative cooperativity.\",\n      \"method\": \"Radiolabeled HDL binding assays; Scatchard analysis; infinite dilution dissociation rate method; nonlinear least-squares model fitting\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous quantitative binding analysis with multiple analytical methods confirming negative cooperativity\",\n      \"pmids\": [\"21254782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SR-BI null mice exhibit high prevalence of exencephaly in embryos, associated with reduced cholesterol content in SR-BI-/- embryos; SR-BI is expressed in extraembryonic tissues (parietal yolk sac trophoblast cells) and mediates maternal-fetal cholesterol transport required for neural tube closure.\",\n      \"method\": \"SR-BI-null mouse intercrosses; embryo cholesterol measurement; immunolocalization of SR-BI in extraembryonic tissues; embryonic phenotype analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with biochemical measurement and immunolocalization establishing mechanism\",\n      \"pmids\": [\"23221804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SR-BI in yolk sac trophoblast giant cells mediates maternal provision of vitamin E to the embryo during neural tube closure; SR-BI-/- embryos have very low vitamin E content; maternal alpha-tocopherol supplementation prevented neural tube defects in SR-BI-/- embryos from 54% to 2%.\",\n      \"method\": \"SR-BI-/- mouse model; embryonic vitamin E measurement; ROS measurements; dietary supplementation rescue; gene expression analysis (Pax3, Alx1, Alx3)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO model + biochemical measurement + dietary rescue experiment confirming vitamin E transport role\",\n      \"pmids\": [\"28701710\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SR-B1/SCARB1 is a multiligand membrane receptor that mediates selective bidirectional transport of cholesterol esters and other lipids (including vitamin E and carotenoids) between lipoproteins and cells through a tunnel in its extracellular domain; it forms negatively cooperative, multimeric clusters at the plasma membrane stabilized by a C-terminal leucine zipper and regulated by PDZK1 binding and Nedd4-1-mediated ubiquitination; in endothelial cells it drives LDL transcytosis by recruiting DOCK4 via its cytoplasmic domain to activate RAC1; in macrophages it mediates efferocytosis via PS binding and Src/PI3K/Rac1 signaling and regulates autophagy through PPARα-TFEB and VPS34-Beclin-1 complex recruitment; in steroidogenic and adrenal cells it supplies cholesterol for hormone synthesis; and it also functions as a receptor for anionic phospholipids, apoptotic cells, silica, and as a co-receptor for HCV and Plasmodium entry.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SCARB1 encodes SR-BI, a multiligand cell-surface scavenger receptor that mediates selective, bidirectional transfer of cholesterol esters, vitamin E, and carotenoids between lipoproteins and cells through a hydrophobic tunnel traversing its extracellular domain [PMID:24162852, PMID:9539787, PMID:16380385, PMID:28465440]. In the liver, SR-BI is the principal receptor for selective HDL cholesteryl ester uptake, with its surface abundance controlled by PDZK1-dependent posttranscriptional stabilization, Nedd4-1-mediated ubiquitination at K500/K508, RBFOX2-regulated alternative splicing, and assembly into negatively cooperative, leucine-zipper-stabilized plasma membrane clusters [PMID:15767854, PMID:37863040, PMID:36536133, PMID:31231038, PMID:21254782]. In endothelial cells SR-BI drives LDL transcytosis by recruiting DOCK4 via an eight-amino-acid cytoplasmic motif to activate RAC1, while in macrophages it mediates efferocytosis through phosphatidylserine binding and Src/PI3K/Rac1 signaling and regulates autophagy via PPARα–TFEB transcription and VPS34–Beclin-1 complex recruitment [PMID:31019307, PMID:26059978, PMID:33661763]. SR-BI also functions as a host entry factor for HCV and Plasmodium sporozoites and as a receptor for silica particles that triggers inflammasome activation [PMID:20949066, PMID:18779053, PMID:28147282].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing SR-BI as a specific receptor for anionic phospholipids resolved the question of whether class B scavenger receptors could recognize non-lipoprotein lipid ligands, opening the broader concept of SR-BI as a multiligand receptor.\",\n      \"evidence\": \"Direct binding and competition assays in transfected cells measuring PS and PI binding with quantitative Kd\",\n      \"pmids\": [\"7541795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of anionic phospholipid binding in vivo not tested\", \"No structural insight into lipid recognition domain\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating that SR-BI mediates endocytosis of apoptotic cells established its role beyond lipid transport as a phagocytic receptor, presaging later efferocytosis studies.\",\n      \"evidence\": \"Gain-of-function CHO transfection with apoptotic cell and liposome uptake assays\",\n      \"pmids\": [\"8549669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of apoptotic cell recognition unknown\", \"In vivo relevance to atherosclerosis not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Quantitative metabolic tracing in SR-BI-attenuated mice proved that hepatic SR-BI is the dominant receptor for selective HDL cholesteryl ester clearance in vivo, establishing its central role in reverse cholesterol transport.\",\n      \"evidence\": \"SR-BI att mice with 53% reduced expression; nondegradable radiolabeled HDL tracing showing proportional reduction in hepatic CE uptake\",\n      \"pmids\": [\"9539787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of selective CE uptake unknown\", \"Whether SR-BI mediates whole-particle HDL uptake or only selective lipid transfer not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Two studies defined SR-BI's membrane context: caveolin-1 acts as a negative regulator of SR-BI-mediated selective CE uptake, and SR-BI is required for microvillar channel formation in adrenocortical cells, linking receptor function to plasma membrane ultrastructure.\",\n      \"evidence\": \"Caveolin-1 overexpression in multiple cell lines inhibiting CE uptake; electron microscopy of SR-BI-null adrenal glands lacking microvillar channels\",\n      \"pmids\": [\"11683884\", \"11907136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which SR-BI organizes microvillar channels undefined\", \"Whether caveolin-1 regulation occurs in hepatocytes in vivo not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"SR-BI was shown to deliver HDL-associated estradiol to endothelial eNOS and to serve as a receptor for hypochlorite-modified LDL, broadening the ligand repertoire beyond native lipoproteins and linking SR-BI to vascular signaling.\",\n      \"evidence\": \"SR-BI null mice lacking HDL-estradiol-mediated vasodilation; CHO overexpression with antibody blocking confirming HOCl-LDL recognition\",\n      \"pmids\": [\"12750408\", \"12968020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of estradiol transfer not identified\", \"Whether oxidized LDL binding uses the same tunnel as CE uptake unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"PDZK1 was identified as a PDZ-domain adaptor essential for hepatic SR-BI protein stability, and SR-BI was shown to mediate intestinal vitamin E and lipid absorption, extending its physiological role to the gut.\",\n      \"evidence\": \"PDZK1 KO mice with near-complete hepatic SR-BI protein loss despite normal mRNA; Caco-2 blocking and intestinal SR-BI transgenic mice for vitamin E uptake\",\n      \"pmids\": [\"15767854\", \"16380385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PDZK1 prevents SR-BI degradation not resolved\", \"Whether intestinal SR-BI operates via the same selective uptake mechanism as hepatic SR-BI unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Kinetic studies demonstrated that the vast majority of SR-BI-mediated selective CE uptake occurs at the cell surface rather than via retroendocytosis, refining the mechanistic model of lipid transfer.\",\n      \"evidence\": \"Pulse-chase assay with biotinylated 125I-HDL3 showing HDL resecretion rate >30-fold slower than selective CE uptake\",\n      \"pmids\": [\"16705213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether surface-based transfer requires specific membrane domains not fully resolved\", \"Structural basis of surface transfer mechanism unknown at this point\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"SR-BI was linked to innate immunity and infection: it supplies adrenal cholesterol for glucocorticoid synthesis during endotoxemia and clears hepatic LPS, and it serves as a dual host factor for Plasmodium liver invasion and intracellular development.\",\n      \"evidence\": \"SR-BI null mice with lethal endotoxic shock rescued by corticosterone; RNAi + overexpression + heterozygous mice for Plasmodium infection\",\n      \"pmids\": [\"18064300\", \"18779053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of LPS clearance by SR-BI not defined\", \"Whether Plasmodium exploits lipid transfer function or a separate binding site unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Rigorous binding analysis established that SR-BI exhibits negatively cooperative HDL binding, implying functional receptor oligomerization at the membrane and explaining complex binding kinetics observed in earlier studies.\",\n      \"evidence\": \"Radiolabeled HDL binding with Scatchard analysis and infinite dilution dissociation rate method confirming negative cooperativity\",\n      \"pmids\": [\"21254782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural arrangement of SR-BI oligomers unknown\", \"Whether negative cooperativity extends to all ligand classes not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"SR-BI in extraembryonic tissues was shown to mediate maternal-to-fetal cholesterol and later vitamin E transport required for neural tube closure, establishing a developmental role.\",\n      \"evidence\": \"SR-BI null embryos with exencephaly and reduced cholesterol; dietary vitamin E supplementation rescuing NTDs from 54% to 2%\",\n      \"pmids\": [\"23221804\", \"28701710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SR-BI transports other essential lipids during embryogenesis not examined\", \"Human relevance of this developmental phenotype not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Homology modeling from the LIMP-2 crystal structure combined with SR-BI mutagenesis revealed a hydrophobic tunnel traversing the extracellular domain through which cholesterol esters are transferred from lipoprotein to the plasma membrane, providing the first structural explanation for selective lipid uptake.\",\n      \"evidence\": \"LIMP-2 crystal structure; SR-BI homology model; tunnel-disrupting mutations abolishing CE uptake\",\n      \"pmids\": [\"24162852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct SR-BI crystal structure available\", \"Dynamics of lipid transit through the tunnel not characterized\", \"Whether all lipid ligands use the same tunnel unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mechanistic dissection of macrophage efferocytosis showed that SR-BI binds phosphatidylserine on apoptotic cells and signals through Src→PI3K→Rac1 to drive engulfment, with SR-BI hematopoietic deficiency causing increased atherosclerotic necrosis in vivo.\",\n      \"evidence\": \"SR-BI KO macrophages with pharmacological Src/PI3K/Rac1 inhibition; bone marrow transplantation in ApoE−/− and LDLR−/− mice\",\n      \"pmids\": [\"26059978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SR-BI efferocytosis and lipid uptake functions are structurally separable unknown\", \"Identity of co-receptors in efferocytosis signaling not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple discoveries in 2017 revealed that endothelial SR-BI drives LDL transcytosis via DOCK4/RAC1 recruitment to its cytoplasmic tail promoting atherosclerosis, that SR-BI recognizes silica through an extracellular α-helix triggering inflammasome activation, and that SR-BI mediates carotenoid uptake and dynamin-dependent HDL transcytosis across brain endothelium.\",\n      \"evidence\": \"Domain mutagenesis and DOCK4 interaction in endothelial monolayers; expression cloning and SR-BI KO for silica recognition; functional assays with WT vs. exon-4-deleted SCARB1 for carotenoid uptake; siRNA and pharmacological inhibitor panel for brain endothelial HDL transcytosis\",\n      \"pmids\": [\"31019307\", \"28147282\", \"28465440\", \"29163190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOCK4-dependent transcytosis pathway operates in brain endothelium not tested\", \"Crystal structure of SR-BI silica-binding helix not determined\", \"Mechanism of carotenoid transfer through the tunnel not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Single-molecule imaging revealed that SR-BI forms large metastable clusters at the plasma membrane via a C-terminal leucine zipper, and that multimerization prevents internalization and is essential for receptor function, unifying earlier observations of negative cooperativity and surface-based lipid transfer.\",\n      \"evidence\": \"Single-chain antibody live-cell imaging; single-molecule tracking; leucine zipper mutagenesis causing rapid internalization\",\n      \"pmids\": [\"31231038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise oligomeric stoichiometry not determined\", \"How PDZK1 binding interfaces with cluster formation not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"HMGB1 nuclear translocation triggered by LDL requires SR-BI in endothelial cells, creating a positive feedback loop where HMGB1 stabilizes SREBP2 to increase SR-BI expression and sustain LDL transcytosis.\",\n      \"evidence\": \"siRNA knockdown, TIRF microscopy, endothelial HMGB1 KO mice with aortic LDL accumulation measurements\",\n      \"pmids\": [\"33054399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this feedback loop operates in non-endothelial cells unknown\", \"Direct physical interaction between HMGB1 and SR-BI not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SR-BI was discovered to regulate macrophage autophagy through two mechanisms—PPARα-dependent TFEB transcription and direct recruitment of VPS34–Beclin-1 to autophagosomal cholesterol domains—explaining how SR-BI deficiency promotes foam cell formation and apoptosis.\",\n      \"evidence\": \"SR-BI KO macrophages; co-IP of VPS34–Beclin-1; VPS34 activity assays; Tfeb and Vps34 overexpression rescue\",\n      \"pmids\": [\"33661763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagy regulation is specific to macrophages or general unknown\", \"How SR-BI cholesterol domains are organized on autophagosomes not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"RBFOX2-dependent alternative splicing of Scarb1 in the liver was identified as a regulatory layer altered in obesity, with splice-switching oligonucleotides rescuing hepatic lipid homeostasis, revealing a post-transcriptional control axis distinct from PDZK1-mediated protein stabilization.\",\n      \"evidence\": \"Enhanced iCLIP of RBFOX2 in mouse liver; RBFOX2 conditional KO; splice-switching oligonucleotides correcting Scarb1 isoform ratio\",\n      \"pmids\": [\"36536133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional difference between Scarb1 splice isoforms not fully characterized\", \"Whether RBFOX2-mediated splicing is conserved in human liver not confirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies refined SR-BI regulation: Nedd4-1 ubiquitinates SR-BI at K500/K508 to promote its degradation (counteracted by lipocalin-2), and intestinal FXR–bile acid signaling drives SR-BI expression in enterocytes to regulate chylomicron secretion.\",\n      \"evidence\": \"K500A/K508A knock-in mice and hepatocyte Lcn2 KO/OE for ubiquitination; intestinal SR-BI KO and FMT with bile acid quantification for FXR regulation\",\n      \"pmids\": [\"37863040\", \"37160898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other E3 ligases also target SR-BI unresolved\", \"How ubiquitination at K500/K508 interfaces with leucine zipper-mediated clustering unknown\", \"Whether FXR-driven intestinal SR-BI regulation affects systemic vitamin E status not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution crystal or cryo-EM structure of SR-BI itself—rather than a LIMP-2-based homology model—is needed to define the lipid tunnel geometry, explain ligand selectivity, and map the silica-binding and PS-binding interfaces.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental SR-BI structure available\", \"Structural basis of negative cooperativity and leucine zipper-mediated clustering unresolved\", \"Whether the DOCK4-binding cytoplasmic motif and PDZK1-binding C-terminus create allosteric cross-talk is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 8, 11, 19, 21]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 2, 7, 18]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 8, 18, 31, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 4, 23, 30]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [16, 19, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 8, 11, 18, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 7, 8, 11, 27, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 17, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PDZK1\",\n      \"DOCK4\",\n      \"RAC1\",\n      \"NEDD4\",\n      \"VPS34\",\n      \"BECN1\",\n      \"CAV1\",\n      \"RBFOX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}