Affinage

ANGPTL8

Angiopoietin-like protein 8 · UniProt Q6UXH0

Length
198 aa
Mass
22.1 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANGPTL8 is a feeding-induced, secreted hepatokine/adipokine that controls the partitioning of postprandial triglycerides between storage and oxidative tissues by regulating lipoprotein lipase (LPL) activity (PMID:24043787, PMID:32730227). ANGPTL8 has no intrinsic LPL-inhibitory activity on its own; it must physically bind ANGPTL3 to form the active inhibitory complex, which dramatically enhances ANGPTL3's ability to bind and inhibit LPL while reciprocally increasing ANGPTL8 secretion, with the inhibitory motif residing in the ANGPTL8 N-terminus (PMID:28413163, PMID:29031715). Hepatic ANGPTL8, acting with ANGPTL3, suppresses intravascular LPL in oxidative tissues such as heart and skeletal muscle in an endocrine manner, while adipose ANGPTL8 enhances local LPL activity by inhibiting ANGPTL4, together routing dietary fat toward adipose storage (PMID:32730227, PMID:26687026); human genetic mimicry indicates the ANGPTL3–ANGPTL8 complex also inhibits endothelial lipase (PMID:36372100). In adipocytes, ANGPTL8 promotes adipogenic differentiation and lipid accumulation and restrains intracellular lipolysis (PMID:28528274, PMID:38272177), and an autocrine/paracrine adipocyte pool influences glucose tolerance, adipose inflammation, and energy expenditure (PMID:39640567). Clean knockout and overexpression studies establish that ANGPTL8 is not required for glucose homeostasis or beta-cell proliferation (PMID:24043787, PMID:25417115, PMID:27410263). Independent of its lipase-regulating role, intracellular ANGPTL8 self-oligomerizes via its N-terminal domain and, together with p62/SQSTM1, targets IKKγ (NEMO) for selective autophagic degradation, providing negative feedback on TNFα-induced NF-κB inflammatory signaling (PMID:29255244). Secreted ANGPTL8 also signals through the paired Ig-like receptors PirB/LILRB2/LILRB3 to reset the hepatic circadian clock, restrain pathological cardiac hypertrophy via Akt/GSK-3β, drive hepatic stellate cell activation and liver fibrosis, and damage neuronal synaptic integrity in diabetic conditions (PMID:31388006, PMID:35851270, PMID:36031141, PMID:39095838). ANGPTL8 expression is transcriptionally activated by HNF-1α and HNF-4α and induced by insulin/feeding signals, and is suppressed by AMPK, repressive chromatin via ZNF638/HDAC1, and the microRNAs miR-221-3p and miR-143-3p (PMID:32561878, PMID:35325025, PMID:32154742, PMID:26254015, PMID:38211696, PMID:28938482, PMID:30261196).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2013 High

    Established the core physiological function of ANGPTL8 in lipid partitioning and ruled out an obligatory role in glucose handling, framing it as a lipid-metabolic rather than glucoregulatory factor.

    Evidence Angptl8 knockout mice with LPL activity, VLDL secretion, tissue TG uptake, and glucose/insulin tolerance assays

    PMID:24043787 PMID:25417115

    Open questions at the time
    • Did not identify the molecular partner required for LPL inhibition
    • Tissue-specific contributions not yet dissected
  2. 2014 High

    Closed off the controversial hypothesis that ANGPTL8 drives pancreatic beta-cell proliferation, redirecting the field toward its lipid function.

    Evidence Angptl8 KO and liver overexpression with beta-cell proliferation quantification under insulin-resistance models

    PMID:25417115 PMID:27410263

    Open questions at the time
    • Did not explain residual metabolic phenotypes of ANGPTL8 manipulation
  3. 2015 Medium

    Showed where ANGPTL8 acts within the LPL system, revealing tissue-selective suppression of LPL in oxidative muscle and defining a druggable epitope.

    Evidence Lipasin-KO mice, tissue-specific LPL assays, monoclonal antibody with epitope mapping (EIQVEE), and AMPK/LXR/SREBP-1 pharmacology in hepatocytes

    PMID:26254015 PMID:26687026

    Open questions at the time
    • Mechanism of tissue selectivity not resolved
    • AMPK regulation shown only in cell culture
  4. 2017 High

    Solved the central mechanistic puzzle of why ANGPTL8 is inactive alone by demonstrating it must form a complex with ANGPTL3 to inhibit LPL, with the inhibitory motif in its N-terminus.

    Evidence Co-IP and NanoBiT interaction assays, blocking/mutant antibodies, ANGPTL3 LPL-inhibitory mutant, and in vivo epistasis in Angptl8 KO mice

    PMID:28413163 PMID:29031715

    Open questions at the time
    • Structural basis of complex-induced LPL inhibition not resolved
    • Stoichiometry of the active complex not defined
  5. 2017 High

    Uncovered a wholly intracellular, lipase-independent function of ANGPTL8 as a negative regulator of NF-κB inflammation via selective autophagy.

    Evidence siRNA/CRISPR, Co-IP, autophagic flux assays, N-terminal oligomerization mutagenesis, and in vivo LPS challenge identifying the ANGPTL8–p62–IKKγ axis

    PMID:29255244

    Open questions at the time
    • How a secreted protein accesses the cytosolic autophagy machinery not explained
    • Relationship between intracellular and secreted pools unclear
  6. 2018 Medium

    Extended ANGPTL8 into disease biology by linking it to lipogenesis and HCC proliferation through C-terminal binding to nuclear SREBP1.

    Evidence Co-IP with C-terminal domain mapping, TALEN KO, metabolomics, and tumor proliferation/growth assays

    PMID:29663480

    Open questions at the time
    • Single-lab Co-IP without reciprocal structural validation
    • In vivo tumor relevance limited
  7. 2019 Medium

    Identified the first cell-surface receptor for ANGPTL8 (PirB) and connected ANGPTL8 to food-entrained circadian clock resetting.

    Evidence Mouse feeding/fasting experiments, receptor identification, kinase/Per1 reporter signaling analysis, and in vivo ANGPTL8 inhibition

    PMID:31388006

    Open questions at the time
    • Direct ANGPTL8–PirB binding affinity and structure not established
    • Signaling intermediates incompletely defined
  8. 2020 High

    Resolved how the two tissue pools of ANGPTL8 coordinate postprandial TG flux through opposing actions on ANGPTL3/4 and defined the transcriptional control of feeding-induced expression.

    Evidence Tissue-specific KO mice, intravascular LPL assays, A8/A4 co-expression, insulin clamps, and HNF-1α/HNF-4α/C/EBPβ promoter, EMSA, ChIP, and reporter analyses

    PMID:32154742 PMID:32561878 PMID:32730227 PMID:35325025

    Open questions at the time
    • Quantitative balance between endocrine and paracrine pools not measured
    • Insulin/AKT signaling effects (idx 10) need stronger in vivo support
  9. 2022 Medium

    Broadened the LILRB/PirB receptor axis to multiple organ pathologies, showing ANGPTL8 signals through distinct receptors to control cardiac hypertrophy, liver fibrosis, and HCC immune evasion.

    Evidence IP-MS/Co-IP receptor screens, recombinant ANGPTL8 treatment, antibody/siRNA blockade, AAV-mediated liver-specific restoration, and disease mouse models

    PMID:35851270 PMID:36031141 PMID:37188659

    Open questions at the time
    • Receptor selectivity (LILRB2 vs LILRB3 vs PirB) across tissues not mechanistically explained
    • Direct binding interfaces not structurally defined
  10. 2022 Medium

    Defined the substrate range of the ANGPTL3–ANGPTL8 complex in humans and the role of ANGPTL8 in adipocyte differentiation.

    Evidence Large-scale human genetic mimicry analysis (UK Biobank + European cohorts) and ANGPTL8 KO/Wnt-pathway rescue in MSC adipogenic differentiation

    PMID:36034432 PMID:36372100

    Open questions at the time
    • EL inhibition is inferred from genetics, not direct biochemistry
    • Wnt-pathway mechanism shown only in MSC differentiation context
  11. 2024 Medium

    Refined the adipose-autonomous and inflammatory roles of ANGPTL8 and identified chromatin-level (ZNF638/HDAC1) repression as an estrogen-dependent control of postprandial TG.

    Evidence Adipocyte-specific inducible KO, preadipocyte knockdown with RNA-seq, septic liver-injury KO with PGC1α/PPARα analysis, neuron-specific and PirB KO behavioral models, and ZNF638 adipose KO with ANGPTL8 neutralization

    PMID:38211696 PMID:38272177 PMID:39019343 PMID:39095838 PMID:39640567

    Open questions at the time
    • Integration of secreted vs intracellular roles across tissues remains incomplete
    • Neuronal and hepatic receptor signaling lack structural detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single secreted protein switches between forming the ANGPTL3 lipase-inhibitory complex, acting intracellularly in p62-dependent autophagy, and signaling through LILRB/PirB receptors — and the structural basis of each — remains unresolved.
  • No structure of the ANGPTL3–ANGPTL8 complex or of ANGPTL8–LILRB binding
  • Mechanism partitioning ANGPTL8 between secreted and intracellular pools unknown
  • Direct biochemical demonstration of endothelial lipase inhibition lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1
Partners
ANGPTL3ANGPTL4IKBKGLILRB2LILRB3PIRBSQSTM1SREBF1
Complex memberships
ANGPTL3-ANGPTL8 complexANGPTL8-p62/SQSTM1 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 ANGPTL8 knockout mice show reduced VLDL secretion and increased lipoprotein lipase (LPL) activity in the fed state, demonstrating that ANGPTL8 is required for directing fatty acids to adipose tissue for storage during the fasting-to-refeeding transition. Despite increased LPL activity, TG uptake is selectively reduced in adipose tissue but preserved in heart, indicating tissue-specific action. Angptl8 knockout mouse model; plasma TG measurements, LPL activity assay, VLDL secretion assay, tissue TG uptake assay Proceedings of the National Academy of Sciences of the United States of America High 24043787
2013 Angptl8 knockout mice show no alterations in glucose homeostasis on chow or high-fat diet, indicating ANGPTL8 is not required for glucose metabolism, contradicting earlier claims of a role in insulin secretion. Glucose tolerance test, insulin tolerance test in Angptl8 knockout mice on chow and high-fat diets Proceedings of the National Academy of Sciences of the United States of America High 24043787 25417115
2017 ANGPTL8 requires ANGPTL3 to inhibit LPL and raise plasma triglycerides; ANGPTL8 alone is inactive despite possessing a functional LPL inhibitory motif. Coexpression of ANGPTL3 and ANGPTL8 produces a far more efficacious increase in plasma TG than ANGPTL3 alone. An antibody to the C-terminus of ANGPTL8 reversed LPL inhibition without disrupting the ANGPTL8:ANGPTL3 complex, placing the inhibitory motif in the N-terminus of ANGPTL8. Mouse overexpression experiments, ANGPTL3 blocking antibody, ANGPTL3 LPL-inhibitory mutant, ANGPTL8 C-terminal antibody, LPL activity assays Journal of lipid research High 28413163
2017 ANGPTL8 physically binds ANGPTL3 (co-IP, NanoBiT split-luciferase), and this complex dramatically increases ANGPTL3's ability to bind and inhibit LPL compared to either protein alone. Co-expression with ANGPTL3 also greatly enhances secretion of ANGPTL8. Co-immunoprecipitation, NanoBiT split-luciferase protein interaction assay, LPL activity assays, adenovirus ANGPTL3 overexpression in Angptl8 knockout mice Molecular metabolism High 29031715
2017 Intracellular ANGPTL8 functions as a negative feedback regulator of TNFα-induced NF-κB activation by facilitating selective autophagic degradation of IKKγ (NEMO). Mechanistically, ANGPTL8 self-oligomerizes via its N-terminal domain, forms a complex with p62/SQSTM1, and the resulting ANGPTL8-p62 platform recruits IKKγ for autophagic degradation. N-terminal self-oligomerization is essential for this function. siRNA knockdown, CRISPR knockout, co-immunoprecipitation, autophagic flux assays, N-terminal domain mutagenesis, in vivo LPS injection in mice Nature communications High 29255244
2020 Hepatic ANGPTL8 (acting with ANGPTL3) inhibits intravascular LPL in oxidative tissues in an endocrine fashion to reduce dietary TG delivery, while adipose-tissue ANGPTL8 enhances local LPL activity by autocrine/paracrine inhibition of ANGPTL4. These combined actions coordinate postprandial TG partitioning. Liver-specific and adipose-specific Angptl8 knockout mice; intravascular LPL activity assays; plasma TG measurements; co-expression of A8 and A4 in cultured cells measuring A4 secretion and A4-mediated LPL inhibition JCI insight High 32730227
2019 ANGPTL8 resets diurnal rhythms of hepatic clock and metabolic genes in mice by signaling through the membrane receptor PirB (paired Ig-like receptor B), inducing phosphorylation of kinases and transcription factors and transiently activating the core clock gene Per1. Inhibition of ANGPTL8 signaling partially blocks food-entrained resetting of the liver clock. Mouse feeding/fasting experiments, receptor identification (PirB), signaling pathway analysis (kinase phosphorylation), Per1 reporter assays, ANGPTL8 inhibition in vivo Nature communications Medium 31388006
2018 HCC-associated protein TD26 (ANGPTL8) interacts via its C-terminus (aa 121–198) with the truncated nuclear form of SREBP1 (nSREBP1), not full-length SREBP1, blocking AMPK-mediated inhibition of SREBP1 activity, resulting in increased lipogenesis and tumor cell proliferation. Co-immunoprecipitation, domain mapping (C-terminal truncation), TALEN-based knockout, metabolomics, functional proliferation and tumor growth assays Hepatology (Baltimore, Md.) Medium 29663480
2015 ANGPTL8 (Lipasin) suppresses LPL activity specifically in cardiac and skeletal muscles (not white adipose tissue) postprandially, as shown by elevated postprandial cardiac and skeletal muscle LPL activity in lipasin-deficient mice. A monoclonal antibody targeting the epitope EIQVEE in ANGPTL8 lowered serum triglycerides by increasing postprandial cardiac LPL activity. Lipasin-knockout mice, monoclonal antibody generation, epitope mapping, tissue-specific LPL activity assay (heart, skeletal muscle, WAT), postprandial TG measurement Scientific reports Medium 26687026
2014 ANGPTL8 overexpression in mouse liver doubles plasma triglycerides but does not induce beta cell expansion or alter glucose metabolism. Angptl8 knockout mice undergo entirely normal beta cell expansion in response to insulin resistance (high-fat diet or S961 insulin receptor antagonist), establishing that ANGPTL8 does not control pancreatic beta cell proliferation. Angptl8 knockout mice; liver overexpression; high-fat diet and S961 insulin receptor antagonist models; beta cell proliferation quantification Cell High 25417115 27410263
2020 ANGPTL8 overexpression enhances insulin-stimulated AKT phosphorylation (improving insulin sensitivity) via the PI3K/AKT signaling pathway in mouse primary hepatocytes and in vivo. Site-directed mutagenesis identified Ser94 and Thr98 as key residues for ANGPTL8-mediated AKT activation. Hydrodynamic tail-vein transfection, in vitro mRNA overexpression, siRNA knockdown in primary hepatocytes, DNA point mutation and fragment truncation, AKT phosphorylation assay Gene Medium 32344005
2015 AMPK activation (by AICAR or metformin) suppresses ANGPTL8 expression induced by the LXR/SREBP-1 signaling pathway in hepatocytes. SREBP-1c siRNA knockdown shows that AICAR's inhibitory effect on ANGPTL8 is most pronounced via SREBP-1, and PPARα phosphorylation by AMPK is also involved. HepG2 cell culture with pharmacological agents (AICAR, metformin, T0901317 LXR agonist), siRNA knockdown of SREBP-1, mRNA expression quantification, PPARα inhibitor experiments Molecular and cellular endocrinology Medium 26254015
2020 Insulin acutely increases Angptl8 expression in liver and adipose tissue via CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor; glucose further enhances Angptl8 expression in adipose tissue in the presence of insulin. AMPK activation antagonizes the insulin effect on Angptl8 expression in hepatocytes and adipocytes. In vivo insulin clamp experiments in mice, primary and cultured hepatocyte and adipocyte experiments, AMPK pathway analysis, bioinformatic and luciferase reporter assays for transcriptional control American journal of physiology. Endocrinology and metabolism Medium 32154742
2020 Transcription factor HNF-1α directly binds the Angptl8 promoter (at -84/-68 bp) and is required for refeeding-induced increases in hepatic Angptl8 expression. HNF-1α expression increases after short-term refeeding in parallel with Angptl8 upregulation, and silencing HNF-1 abolishes insulin-induced Angptl8 expression in primary hepatocytes. Promoter deletion analysis, luciferase reporter assay, HNF-1 binding site mutagenesis, siRNA knockdown of HNF-1 in hepatoma cells and primary hepatocytes, EMSA (electrophoretic mobility shift assay), chromatin immunoprecipitation (ChIP) Scientific reports High 32561878
2016 Angptl8 knockdown in 3T3-L1 adipocytes reduces stored triglycerides and enhances intracellular lipolysis (increased NEFA release), and alters cellular phospholipid composition (reduced alkyl-PCs and PE plasmalogens). Angptl8 mRNA is suppressed by lipolysis-inducing agents (isoproterenol, forskolin), supporting its role as an insulin-regulated inhibitor of intracellular lipolysis in adipocytes. Lentiviral stable knockdown in 3T3-L1 cells, lipidomics/lipidome analysis, NEFA release lipolysis assay, lipid droplet morphology, gene expression profiling Chemistry and physics of lipids Medium 28528274
2016 Hepatocyte nuclear factor-4α (HNF4α) binds the ANGPTL8 promoter and drives ANGPTL8 expression in hepatocytes. Sebacic acid (from royal jelly) reduces HNF4α protein levels and its binding to the ANGPTL8 promoter, thereby downregulating ANGPTL8 expression. Reporter assay, HNF4α siRNA knockdown, HNF4α binding site identification in ANGPTL8 promoter, measurement of HNF4α-promoter binding Bioscience, biotechnology, and biochemistry Medium 35325025
2017 miR-221-3p, induced by inflammatory stimuli (macrophage-conditioned medium/LPS) in adipocytes, targets the ANGPTL8 mRNA 3'UTR and reduces adipocyte ANGPTL8 protein expression, establishing miR-221-3p as a post-transcriptional regulator of ANGPTL8 under inflammatory conditions. miRNA target prediction, 3'UTR interaction assay, miR-221-3p mimic/inhibitor transfection in adipocytes, protein and mRNA quantification, correlation analysis in adipose tissue biopsies The Journal of clinical endocrinology and metabolism Medium 28938482
2018 miR-143-3p targets the ANGPTL8 3'UTR and downregulates ANGPTL8 transcript and protein in hepatocytes. Inhibition of miR-143-3p amplifies ANGPTL8 responses to hyperglycemic, hyperinsulinemic, and proinflammatory stimuli in HepG2 cells. Target prediction algorithm, 3'UTR reporter assay (exogenous miR-143-3p binding), mimic/siRNA transfection in HepG2 cells, pharmacological stimulation (glucose, insulin, LPS) Gene Medium 30261196
2022 ANGPTL8 binds to the receptor LILRB2/PIRB and activates the ROS/ERK signaling pathway in hepatocytes, promoting autophagy and hepatocellular carcinoma cell proliferation. ANGPTL8-LILRB2/PIRB interaction also polarizes macrophages toward an immunosuppressive M2 phenotype and recruits immunosuppressive T cells. RNA-seq, protein array, co-immunoprecipitation, flow cytometry, in vitro and in vivo HCC experiments, ANGPTL8 KO mice Oncogenesis Medium 37188659
2022 ANGPTL8 acts as a negative regulator of pathological cardiac hypertrophy by binding to the paired Ig-like receptor LILRB3 (PIRB) and inhibiting Akt/GSK-3β activation in cardiomyocytes. Recombinant ANGPTL8 and ANGPTL8 overexpression attenuate Ang II-induced cardiomyocyte enlargement, and these effects are blocked by anti-LILRB3 antibody or LILRB3 siRNA. RNA-seq and immunoprecipitation-mass spectrometry receptor screening, recombinant protein treatment, ANGPTL8 overexpression, Akt activator (SC-79) rescue experiment, anti-LILRB3 antibody and siRNA-LILRB3 blockade, Ang II and TAC cardiac hypertrophy mouse models Cell death & disease Medium 35851270
2022 Liver-derived ANGPTL8 activates hepatic stellate cells (HSCs) by interacting with the LILRB2 receptor to induce ERK signaling and increase expression of profibrotic genes, promoting NAFLD-associated liver fibrosis. Co-IP, protein array, RNA-sequencing, AAV8-mediated liver-specific restoration of ANGPTL8 in KO mice, KO mouse disease models (HFD, HFHC, CCL4), immunohistochemistry, western blot Journal of advanced research Medium 36031141
2024 ANGPTL8 is secreted by neurons into the hippocampus in diabetic mice, and acts through its receptor PirB in parallel on neurons and microglia: downregulating synaptic/axonal markers in neurons and upregulating proinflammatory cytokines in microglia. PirB knockout mice were resistant to ANGPTL8-induced neuroinflammation and synaptic damage. Neuron-specific Angptl8 KO, PirB KO mice, recombinant ANGPTL8 protein treatment of primary neurons and microglia, Barnes Maze and novel object recognition behavioral tests, PirB pathway blockade Journal of neuroinflammation Medium 39095838
2016 The ANGPTL8 R59W variant (rs2278426) is associated with increased levels of cleaved ANGPTL3 in plasma, suggesting this variant affects ANGPTL8-mediated activation/cleavage of ANGPTL3. Genetic association study with biochemical measurement of cleaved ANGPTL3; ANGPTL8 transcript and protein response to glucose and insulin in cell culture Molecular genetics and metabolism Low 27117576
2018 GLP-1 receptor agonists (exendin-4, liraglutide) stimulate ANGPTL8 production in hepatocytes via the PI3K/Akt pathway in a GLP-1 receptor-dependent manner, as demonstrated by blockade with GLP-1R antagonist (exendin 9-39) and PI3K inhibitor (LY294002). HepG2 cell treatment with GLP-1R agonists, GLP-1R antagonist and PI3K inhibitor co-treatment, ANGPTL8 mRNA and protein measurement; clinical trial measuring serum ANGPTL8 before/after exenatide treatment Peptides Medium 30003931
2016 Hepatic Angptl8 expression is rhythmically expressed, regulated by liver X receptor alpha (LXRα) during feeding and glucocorticoid receptor (GR) during fasting. Angptl8 mRNA is highly unstable, contributing to its daily oscillation. Intracellular (non-secreted) Angptl8 also regulates hepatic lipid homeostasis, as demonstrated by ectopic expression of a non-secreted Angptl8 mutant (Δ25-Angptl8). Adenoviral Angptl8 delivery in mice, non-secreted Angptl8 mutant (Δ25) overexpression, mRNA stability assays, LXRα and GR signaling experiments, plasma TG and NEFA measurements Scientific reports Medium 27845381
2022 ANGPTL8 promotes the differentiation of mesenchymal stem cells (MSCs) into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and C/EBPα expression. This effect is reversed by the Wnt/β-Catenin pathway activator LiCl and a GSK3β inhibitor (CHIR99021), establishing the mechanistic pathway. ANGPTL8 KO mice (NCD and HFD), ovariectomy model, isolated MSC adipogenic differentiation assay, Wnt/β-Catenin pathway activators (LiCl, CHIR99021), Oil Red O staining, organ TG measurement Frontiers in endocrinology Medium 36034432
2024 ANGPTL8 knockout in adipose tissue (AT-A8-KO) in mice on a high-fat high-fructose diet improves glucose tolerance, insulin-stimulated glucose uptake in adipose tissue, reduces visceral adipose inflammation (crown-like structures, MCP-1, leptin), and increases energy expenditure, establishing an autocrine/paracrine role of adipocyte ANGPTL8 in glucose and energy homeostasis. Adipocyte-specific inducible Angptl8 KO mice on HFHF diet; glucose tolerance test, insulin sensitivity test, tissue glucose uptake, indirect calorimetry, histological analysis, plasma cytokine measurements iScience Medium 39640567
2024 ANGPTL8 deficiency in septic mice activates the PGC1α/PPARα pathway, reduces hepatic lipid accumulation and lipid peroxidation, improves fatty acid oxidation, and increases survival. LPS-induced ANGPTL8 expression is dependent on TNF-α signaling. Angptl8 KO mice with LPS-induced liver injury model, survival analysis, hepatic lipid assays, fatty acid oxidation gene expression, PGC1α/PPARα pathway analysis, TNF-α pathway inhibition Journal of lipid research Medium 39019343
2022 Human genetic mimicry analysis shows that the ANGPTL3-ANGPTL8 complex inhibits both LPL and endothelial lipase (EL/LIPG) in humans. The ANGPTL8 R59W substitution shows higher concordance with EL activity changes than LPL activity, while a rare protein-truncating ANGPTL8 variant shows LPL-specific effects, indicating the complex has both LPL and EL as substrates. Genetic mimicry analysis using UK Biobank (n>110,000) and 11 European populations; variant instrumental variable analysis; 248 metabolic parameters Journal of lipid research Medium 36372100
2024 ANGPTL8 knockdown in mouse subcutaneous preadipocytes reduces adipogenic differentiation, cellular TG accumulation, and isoproterenol-stimulated lipolysis. RNA-seq shows ANGPTL8 KD impedes early expression of adipogenic and insulin signaling genes including PPARγ, and reduces insulin-mediated Akt phosphorylation at early stages of differentiation. siRNA knockdown in primary mouse subcutaneous preadipocytes, RNA-seq at differentiation days 0/2/4/7, lipid droplet and TG assays, Akt phosphorylation assay Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 38272177
2024 ZNF638 acts as a transcriptional repressor of ANGPTL8 in adipose tissue by recruiting HDAC1 for histone deacetylation at the Angptl8 locus. ZNF638 adipose-specific KO increases ANGPTL8 in female mice and causes refeeding-induced TG elevation, which is abolished by neutralizing circulating ANGPTL8, establishing ZNF638-ANGPTL8 as an estrogen-dependent axis regulating postprandial TG metabolism. Adipose-specific ZNF638 KO mice, adenoviral ZNF638 overexpression, RNA-seq, HDAC1 recruitment assay, ANGPTL8 neutralizing antibody, LPL activity assay, postprandial TG measurement Metabolism: clinical and experimental Medium 38211696
2023 The ANGPTL8 R59W variant is associated with increased circulating TNFα and IL-7 and increased NF-κB p65 activity. In vitro studies in HepG2 cells show enhanced phosphorylation of NF-κB pathway proteins and increased NF-κB luciferase reporter activity with the R59W variant, especially under TNFα stimulation. Structural modeling indicates the R59W change alters ANGPTL8's transient binding dynamics. Cohort genotyping, ELISA of inflammatory markers, HepG2 overexpression with luciferase NF-κB assay, western blotting of NF-κB pathway proteins, structural modeling Cells Low 37947641

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proceedings of the National Academy of Sciences of the United States of America 283 24043787
2012 Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. American journal of physiology. Endocrinology and metabolism 267 22569073
2017 ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. Journal of lipid research 179 28413163
2014 ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell 179 25417115
2017 ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Molecular metabolism 160 29031715
2017 ANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ. Nature communications 96 29255244
2016 Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: animal and human studies. Scientific reports 90 27045862
2020 The multi-faces of Angptl8 in health and disease: Novel functions beyond lipoprotein lipase modulation. Progress in lipid research 79 33011191
2022 ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways. Journal of advanced research 76 36031141
2020 ANGPTL8 has both endocrine and autocrine effects on substrate utilization. JCI insight 73 32730227
2015 A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase. Scientific reports 70 26687026
2017 ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice. Endocrinology 68 28204173
2016 Circulating ANGPTL8/Betatrophin Is Increased in Obesity and Reduced after Exercise Training. PloS one 67 26784326
2018 Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia 66 29497783
2016 Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study. Cardiovascular diabetology 66 26739706
2018 ANGPTL8: An Important Regulator in Metabolic Disorders. Frontiers in endocrinology 65 29719529
2015 Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice. Diabetologia 62 25917759
2015 ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β or Akt-FoxO1 pathway in HepG2 cells. Experimental cell research 60 26387753
2019 Angptl8 mediates food-driven resetting of hepatic circadian clock in mice. Nature communications 58 31388006
2017 ANGPTL8 (betatrophin) role in diabetes and metabolic diseases. Diabetes/metabolism research and reviews 56 28722798
2015 AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells. Molecular and cellular endocrinology 56 26254015
2016 Fasting and Feeding Signals Control the Oscillatory Expression of Angptl8 to Modulate Lipid Metabolism. Scientific reports 51 27845381
2018 Hepatocellular Carcinoma-Associated Protein TD26 Interacts and Enhances Sterol Regulatory Element-Binding Protein 1 Activity to Promote Tumor Cell Proliferation and Growth. Hepatology (Baltimore, Md.) 47 29663480
2018 Increased plasma and adipose tissue levels of ANGPTL8/Betatrophin and ANGPTL4 in people with hypertension. Lipids in health and disease 46 29490644
2021 ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease. PLoS genetics 39 33909604
2016 Altered Concentrations in Dyslipidemia Evidence a Role for ANGPTL8/Betatrophin in Lipid Metabolism in Humans. The Journal of clinical endocrinology and metabolism 38 27472196
2016 The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3. Molecular genetics and metabolism 36 27117576
2016 The Effects of Serum ANGPTL8/betatrophin on the Risk of Developing the Metabolic Syndrome - A Prospective Study. Scientific reports 36 27345212
2016 Resolving Discrepant Findings on ANGPTL8 in β-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy. PloS one 36 27410263
2018 CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats. Journal of lipid research 35 30042156
2015 In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats. Diabetologia 33 25720603
2015 Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects. Cardiovascular diabetology 33 26289721
2016 Structural characterization of ANGPTL8 (betatrophin) with its interacting partner lipoprotein lipase. Computational biology and chemistry 30 26908254
2016 Angiopoietin-like protein 8 (ANGPTL8) in pregnancy: a brown adipose tissue-derived endocrine factor with a potential role in fetal growth. Translational research : the journal of laboratory and clinical medicine 30 27469268
2017 ANGPTL8 (Betatrophin) is Expressed in Visceral Adipose Tissue and Relates to Human Hepatic Steatosis in Two Independent Clinical Collectives. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 27 28351093
2017 MicroRNA-221-3p Regulates Angiopoietin-Like 8 (ANGPTL8) Expression in Adipocytes. The Journal of clinical endocrinology and metabolism 26 28938482
2020 ANGPTL8 enhances insulin sensitivity by directly activating insulin-mediated AKT phosphorylation. Gene 25 32344005
2018 The negative effect of ANGPTL8 on HDL-mediated cholesterol efflux capacity. Cardiovascular diabetology 24 30409151
2018 Neuropeptide Y-Positive Neurons in the Dorsomedial Hypothalamus Are Involved in the Anorexic Effect of Angptl8. Frontiers in molecular neuroscience 24 30618603
2020 Regulation of ANGPTL8 in liver and adipose tissue by nutritional and hormonal signals and its effect on glucose homeostasis in mice. American journal of physiology. Endocrinology and metabolism 23 32154742
2017 Visualizing the regulatory role of Angiopoietin-like protein 8 (ANGPTL8) in glucose and lipid metabolic pathways. Genomics 23 28684091
2016 Circulating ANGPTL8/Betatrophin Concentrations Are Increased After Surgically Induced Weight Loss, but Not After Diet-Induced Weight Loss. Obesity surgery 23 26768268
2022 ANGPTL8 is a negative regulator in pathological cardiac hypertrophy. Cell death & disease 22 35851270
2019 ANGPTL8 regulates adipocytes differentiation and adipogenesis in bovine. Gene 22 31048067
2022 Genetic Mimicry Analysis Reveals the Specific Lipases Targeted by the ANGPTL3-ANGPTL8 Complex and ANGPTL4. Journal of lipid research 21 36372100
2021 Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8. The Journal of clinical endocrinology and metabolism 20 33619548
2017 Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition. Chemistry and physics of lipids 20 28528274
2018 GLP-1 receptor agonists stimulate ANGPTL8 production through the PI3K/Akt pathway in a GLP-1 receptor-dependent manner. Peptides 19 30003931
2018 Angiopoietin-like 8 (ANGPTL8) expression is regulated by miR-143-3p in human hepatocytes. Gene 19 30261196
2017 Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus. G3 (Bethesda, Md.) 19 28754724
2020 Predictive values of ANGPTL8 on risk of all-cause mortality in diabetic patients: results from the REACTION Study. Cardiovascular diabetology 18 32746907
2016 The Rise and the Fall of Betatrophin/ANGPTL8 as an Inducer of β-Cell Proliferation. Journal of diabetes research 18 27672665
2024 Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway. Journal of neuroinflammation 17 39095838
2016 ANGPTL8/Betatrophin R59W variant is associated with higher glucose level in non-diabetic Arabs living in Kuwaits. Lipids in health and disease 17 26864934
2019 The Relationship between Circulating ANGPTL8/Betatrophin Concentrations and Adult Obesity: A Meta-Analysis. Disease markers 16 31772689
2017 Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome. Scientific reports 16 28600576
2022 ANGPTL8 promotes adipogenic differentiation of mesenchymal stem cells: potential role in ectopic lipid deposition. Frontiers in endocrinology 15 36034432
2021 Role of ANGPTL8 in NAFLD Improvement after Bariatric Surgery in Experimental and Human Obesity. International journal of molecular sciences 15 34884755
2016 ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells. Oncotarget 15 27823982
2018 A new way to regulate inflammation: selective autophagic degradation of IKKγ mediated by ANGPTL8. Cell stress 14 31225468
2023 Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy. International journal of molecular sciences 12 37762544
2021 Silencing of ANGPTL8 Alleviates Insulin Resistance in Trophoblast Cells. Frontiers in endocrinology 12 34163433
2020 Evidences for Expression and Location of ANGPTL8 in Human Adipose Tissue. Journal of clinical medicine 12 32069954
2023 TDAG51 Attenuates Impaired Lipid Metabolism and Insulin Resistance in Gestational Diabetes Mellitus Through SREBP-1/ANGPTL8 Pathway. Balkan medical journal 11 36960944
2023 Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis. Oncogenesis 11 37188659
2021 ANGPTL8 roles in proliferation, metabolic diseases, hypothyroidism, polycystic ovary syndrome, and signaling pathways. Molecular biology reports 11 33864588
2021 Association of ANGPTL8 and Resistin With Diabetic Nephropathy in Type 2 Diabetes Mellitus. Frontiers in endocrinology 11 34603198
2020 Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver. Scientific reports 11 32561878
2019 Circulating Angiopoietin-like 8 protein (ANGPTL8/Betatrophin) in patients with polycystic ovary syndrome: a systematic review and multi effect size meta-analysis. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 11 30614305
2023 ANGPTL8 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice. Clinical science (London, England : 1979) 10 37294581
2023 Emerging insights into the roles of ANGPTL8 beyond glucose and lipid metabolism. Frontiers in physiology 10 38107478
2021 Evaluation of serum Angiopoietin-like protein 2 (ANGPTL-2), Angiopoietin-like protein 8 (ANGPTL-8), and high-sensitivity C-reactive protein (hs-CRP) levels in patients with gestational diabetes mellitus and normoglycemic pregnant women. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 10 33615956
2020 Association of ANGPTL8 (Betatrophin) Gene Variants with Components of Metabolic Syndrome in Arab Adults. Scientific reports 10 32317770
2023 ANGPTL8 links inflammation and poor differentiation, which are characteristics of malignant renal cell carcinoma. Cancer science 9 36529524
2019 Decreased circulating levels of ANGPTL8 in Graves' disease patients. Hormones (Athens, Greece) 9 30900216
2018 Association between rs2278426 (C/T) and rs892066 (C/G) variants of ANGPTL8 (betatrophin) and susceptibility to type2 diabetes mellitus. Journal of clinical laboratory analysis 9 30191588
2024 ANGPTL8 deficiency attenuates lipopolysaccharide-induced liver injury by improving lipid metabolic dysregulation. Journal of lipid research 8 39019343
2021 Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C Study. Cardiovascular diabetology 8 34167540
2019 Correlation between miR-103 and miR-133a Expression and the Circulating ANGPTL8 in Type 2 Diabetic Patients and Healthy Control Subjects. Clinical laboratory 8 31710446
2018 Biological Pathways Leading From ANGPTL8 to Diabetes Mellitus-A Co-expression Network Based Analysis. Frontiers in physiology 8 30627105
2016 A null mutation in ANGPTL8 does not associate with either plasma glucose or type 2 diabetes in humans. BMC endocrine disorders 8 26822414
2024 Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice. iScience 7 39640567
2023 Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients With Stable Coronary Artery Disease Receiving Statin Therapy. Arteriosclerosis, thrombosis, and vascular biology 7 37259862
2021 ANGPTL8 in cardio-metabolic diseases. Clinica chimica acta; international journal of clinical chemistry 7 34023284
2020 Circulating betatrophin/ANGPTL8 levels correlate with body fat distribution in individuals with normal glucose tolerance but not those with glucose disorders. BMC endocrine disorders 7 32299395
2020 ANGPTL8 Gene Polymorphism rs2278426 Is Related to Carotid Intima-Media Thickness in T2DM. Diabetes, metabolic syndrome and obesity : targets and therapy 7 33244249
2019 Bacteria-Derived Recombinant Human ANGPTL8/Betatrophin Significantly Increases the Level of Triglyceride. The protein journal 7 30929133
2015 A tryptophan derivative TD-26 attenuates thrombus formation by inhibiting both PI3K/Akt signaling and binding of fibrinogen to integrin αIIbβ3. Biochemical and biophysical research communications 7 26278818
2023 Genetic predisposition to nonalcoholic fatty liver disease: insights from ANGPTL8 gene variants in Iranian adults. Lipids in health and disease 6 37679750
2023 The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation. Cells 6 37947641
2022 Royal jelly fatty acids downregulate ANGPTL8 expression through the decrease in HNF4α protein in human hepatoma HepG2 cells. Bioscience, biotechnology, and biochemistry 6 35325025
2020 Angiopoietin-like 8 (ANGPTL8) as a potential predictor of NAFLD in paediatric patients with Prader-Willi Syndrome. Journal of endocrinological investigation 6 33067796
2020 The ANGPTL8 rs2278426 (C/T) Polymorphism Is Associated with Prediabetes and Type 2 Diabetes in a Han Chinese Population in Hebei Province. International journal of endocrinology 6 33343659
2012 RIFL aims to be a new player in lipid metabolism. American journal of physiology. Endocrinology and metabolism 6 22855523
2024 Zinc finger protein ZNF638 regulates triglyceride metabolism via ANGPTL8 in an estrogen dependent manner. Metabolism: clinical and experimental 5 38211696
2024 Silencing ANGPTL8 reduces mouse preadipocyte differentiation and insulin signaling. Biochimica et biophysica acta. Molecular and cell biology of lipids 5 38272177
2023 Adolescent obesity and ANGPTL8: correlations with high sensitivity C-reactive protein, leptin, and chemerin. Frontiers in endocrinology 5 38189043
2022 Effect of physical activity in a weight loss program on circulating total ANGPTL8 concentrations in northern Americans with obesity: A prospective randomized controlled trial. Nutrition, metabolism, and cardiovascular diseases : NMCD 5 35527126
2021 Association of Circulating ANGPTL8 Levels With Renal Dysfunction: A Case-Control Study. Frontiers in public health 5 34557469
2021 ANGPTL8/Betatrophin Improves Glucose Tolerance in Older Mice and Metabolomic Analysis Reveals Its Role in Insulin Resistance in HepG2 Cells. Diabetes, metabolic syndrome and obesity : targets and therapy 5 34703256

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