Affinage

ANGPTL8

Angiopoietin-like protein 8 · UniProt Q6UXH0

Length
198 aa
Mass
22.1 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANGPTL8 is a secreted, insulin-induced regulator of triglyceride partitioning that coordinates lipid trafficking between tissues during the fasting-to-feeding transition. In the fed state, liver-derived ANGPTL8 forms a complex with ANGPTL3 that potently inhibits lipoprotein lipase (LPL) and endothelial lipase in oxidative tissues (heart, skeletal muscle), while adipose-derived ANGPTL8 suppresses ANGPTL4 to locally enhance LPL activity, thereby directing circulating triglycerides to adipose storage (PMID:24043787, PMID:28413163, PMID:32730227, PMID:36372100). Hepatic ANGPTL8 transcription is controlled by insulin-responsive transcription factors HNF-1α and HNF-4α and is antagonized by AMPK signaling (PMID:32561878, PMID:35325025, PMID:32154742). Beyond lipid metabolism, intracellular ANGPTL8 negatively regulates NF-κB signaling by promoting p62-mediated autophagic degradation of IKKγ (PMID:29255244), and extracellular ANGPTL8 signals through LILRB family receptors (PirB/LILRB2/LILRB3) to reset the hepatic circadian clock, promote hepatic stellate cell activation, and suppress pathological cardiac hypertrophy (PMID:31388006, PMID:36031141, PMID:35851270).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2012 High

    Identifying ANGPTL8 as a novel insulin- and refeeding-induced gene with a prolipogenic function established the first functional framework for an uncharacterized protein in adipogenesis and lipid storage.

    Evidence siRNA knockdown in 3T3-L1 adipocytes showing ~35% TG reduction, >100-fold induction during adipogenesis and refeeding in mouse fat and liver

    PMID:22569073

    Open questions at the time
    • No molecular target identified
    • Secreted versus intracellular function not distinguished
    • Mechanism of TG accumulation not resolved
  2. 2013 High

    The knockout mouse demonstrated that ANGPTL8 is required for fasting-to-feeding metabolic transitions, establishing its tissue-selective role in directing dietary triglycerides to adipose tissue via regulation of LPL activity.

    Evidence Angptl8 KO mice with reduced VLDL secretion, increased LPL activity in heart but impaired adipose TG uptake in the fed state

    PMID:24043787

    Open questions at the time
    • Mechanism of LPL inhibition (direct or indirect) not determined
    • Relationship to ANGPTL3 not yet established
  3. 2014 High

    Ruling out ANGPTL8 as a beta cell proliferogen resolved a major controversy and refocused the field on its lipid-metabolic function.

    Evidence Angptl8-null mice showed normal beta cell expansion under HFD and S961-induced insulin resistance; liver ANGPTL8 overexpression doubled TG without affecting beta cells

    PMID:25417115

    Open questions at the time
    • Molecular mechanism of TG elevation by hepatic overexpression not clarified
  4. 2015 High

    Identifying tissue-specific LPL suppression in heart and skeletal muscle by ANGPTL8, and demonstrating therapeutic antibody-mediated TG lowering, defined the physiological sites of ANGPTL8-mediated LPL inhibition.

    Evidence Monoclonal antibody targeting EIQVEE epitope lowered TG; Lipasin-deficient mice showed elevated postprandial LPL in cardiac/skeletal muscle but not WAT

    PMID:26687026

    Open questions at the time
    • Whether ANGPTL8 acts on LPL directly or obligately requires ANGPTL3 not yet resolved
  5. 2015 Medium

    Upstream transcriptional control of ANGPTL8 by LXR/SREBP-1 and suppression by AMPK placed ANGPTL8 within the canonical hepatic lipogenic transcriptional network.

    Evidence LXR agonist and palmitic acid upregulate ANGPTL8 in HepG2; AICAR suppresses via PPARα phosphorylation; SREBP-1 siRNA blocks induction

    PMID:26254015

    Open questions at the time
    • Direct promoter binding by SREBP-1 not demonstrated
    • In vivo validation of SREBP-1-dependent regulation lacking
  6. 2016 Medium

    Demonstration that ANGPTL8 overexpression enhances and knockout attenuates insulin-stimulated Akt/GSK3β/FoxO1 phosphorylation established an intracellular signaling function beyond LPL regulation.

    Evidence TALEN-mediated KO and stable overexpression in HepG2; western blot of PI3K/Akt pathway under normal and insulin-resistant conditions

    PMID:26387753

    Open questions at the time
    • Mechanism by which intracellular ANGPTL8 activates Akt not determined
    • Not replicated in primary hepatocytes at this stage
  7. 2017 High

    Reconstitution of the ANGPTL3–ANGPTL8 complex and demonstration of its obligate partnership for LPL inhibition resolved how ANGPTL8 functions as a secreted lipase inhibitor — it dramatically enhances ANGPTL3's LPL-binding capacity rather than acting independently.

    Evidence Co-IP and NanoBiT split-luciferase confirmed physical interaction; ANGPTL3 raised TG only in presence of ANGPTL8 in vivo; antibody to ANGPTL8 C-terminus blocked LPL inhibition; mutated ANGPTL3 still activated ANGPTL8

    PMID:28413163 PMID:29031715

    Open questions at the time
    • Structural basis of complex formation unknown
    • Stoichiometry of the complex not determined
  8. 2017 High

    Discovery that intracellular ANGPTL8 promotes selective autophagic degradation of IKKγ via p62/SQSTM1 revealed an unexpected anti-inflammatory, NF-κB-regulatory function mechanistically distinct from its extracellular lipase-inhibitory role.

    Evidence Reciprocal Co-IP of ANGPTL8–IKKγ–p62, autophagic flux assays, N-terminal domain mutagenesis abolishing oligomerization and function, in vivo LPS model

    PMID:29255244

    Open questions at the time
    • Whether this function operates in physiological contexts beyond experimental inflammation unknown
    • Relationship between secreted and intracellular pools not clarified
  9. 2018 High

    Interaction of ANGPTL8 C-terminus with nuclear SREBP1 to block AMPK-mediated inhibition linked ANGPTL8 to lipogenesis-dependent tumor cell proliferation in HCC.

    Evidence Co-IP with domain truncation mapping (aa 121–198), AMPK inhibition assays, in vivo tumor growth assays

    PMID:29663480

    Open questions at the time
    • Whether this interaction is relevant outside HCC not established
    • Crystal structure of ANGPTL8–nSREBP1 complex lacking
  10. 2019 High

    ANGPTL8 was found to signal through the PirB/LILRB membrane receptor to reset the hepatic circadian clock via Per1 activation, establishing it as an endocrine entrainment signal linking feeding to peripheral clock resetting.

    Evidence Angptl8 KO and overexpression mice, PirB receptor blocking, circadian gene expression profiling

    PMID:31388006

    Open questions at the time
    • Downstream signaling cascade from PirB to Per1 incompletely characterized
    • Whether ANGPTL8-PirB signaling operates in non-hepatic tissues not determined at this stage
  11. 2020 High

    Tissue-specific knockouts resolved the dual-mode model: hepatic ANGPTL8 acts endocrinally with ANGPTL3 to inhibit LPL in oxidative tissues, while adipose ANGPTL8 acts locally to suppress ANGPTL4 and enhance adipose LPL activity.

    Evidence Liver-specific and adipose-specific Angptl8 KO mice with plasma TG, tissue LPL activity, and cell-based ANGPTL4 secretion assays

    PMID:32730227

    Open questions at the time
    • Molecular mechanism of ANGPTL4 suppression by ANGPTL8 not fully defined
    • Whether ANGPTL8 forms a physical complex with ANGPTL4 unclear
  12. 2020 High

    Identification of HNF-1α binding to a defined promoter element (−84/−68 bp) and its requirement for insulin-induced ANGPTL8 transcription established the core transcriptional mechanism for hepatic ANGPTL8 regulation, complemented by HNF-4α and C/EBPβ as additional transcriptional activators.

    Evidence EMSA and ChIP confirming HNF-1α binding, promoter deletion/mutation, HNF-1 siRNA abolishing insulin induction; HNF-4α identified by siRNA and promoter assay; C/EBPβ identified by insulin clamp and reporter assays

    PMID:32154742 PMID:32561878 PMID:35325025

    Open questions at the time
    • Chromatin-level regulation (enhancers, epigenetic marks) not mapped genome-wide
    • Integration of HNF-1α, HNF-4α, C/EBPβ, and SREBP-1 inputs at the endogenous locus not resolved
  13. 2022 High

    Extension of LILRB receptor signaling to cardiac and hepatic stellate cell contexts — ANGPTL8 binding LILRB3 suppresses cardiac hypertrophy via Akt/GSK3β inhibition, while ANGPTL8 binding LILRB2 activates stellate cells via ERK to promote fibrosis — broadened the receptor-mediated signaling paradigm beyond circadian entrainment.

    Evidence ANGPTL8 KO in Ang II/TAC cardiac models with IP-MS receptor identification and siRNA/blocking antibody confirmation; KO in HFD/CCl4 liver models with AAV8 rescue and Co-IP for LILRB2

    PMID:35851270 PMID:36031141

    Open questions at the time
    • Selectivity determinants for LILRB2 vs LILRB3 binding unknown
    • Whether different LILRB family members produce opposing downstream effects in the same tissue not tested
  14. 2022 Medium

    Human genetic mimicry analysis established that the ANGPTL3–ANGPTL8 complex inhibits endothelial lipase in addition to LPL, with the R59W variant differentially affecting EL versus LPL inhibition, extending the target range of the complex beyond LPL.

    Evidence Variant-specific metabolite profiling in >110,000 UK Biobank individuals and 11 European cohorts

    PMID:36372100

    Open questions at the time
    • No direct enzymatic assay confirming EL inhibition by the purified complex
    • Structural basis for differential R59W effects on EL vs LPL not determined
  15. 2024 Medium

    Neuron-specific ANGPTL8 knockout demonstrated a brain-intrinsic role for ANGPTL8 in diabetic neuroinflammation and synaptic loss via PirB signaling, extending ANGPTL8's paracrine LILRB-mediated functions to the central nervous system.

    Evidence Neuron-specific Angptl8 KO and PirB-/- mice, behavioral testing, synaptic marker and cytokine measurement

    PMID:39095838

    Open questions at the time
    • Whether neuronal ANGPTL8 has physiological roles outside diabetic pathology unknown
    • Downstream signaling cascade from PirB in neurons not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the ANGPTL3–ANGPTL8 complex and how it differentially inhibits LPL versus endothelial lipase; the molecular mechanism by which adipose ANGPTL8 suppresses ANGPTL4; the selectivity determinants for LILRB2 versus LILRB3 receptor engagement; and how intracellular (NF-κB/autophagy, SREBP1) and extracellular (LPL inhibition, LILRB signaling) functions are coordinated from a single gene product.
  • No crystal or cryo-EM structure of ANGPTL3–ANGPTL8 complex
  • Mechanism of ANGPTL4 suppression by ANGPTL8 at the molecular level undefined
  • Partitioning of ANGPTL8 between secreted and intracellular pools not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0048018 receptor ligand activity 4
Localization
GO:0005576 extracellular region 7 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 9 R-HSA-162582 Signal Transduction 8 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 2 R-HSA-9909396 Circadian clock 1
Partners
ANGPTL3ANGPTL4IKBKGLILRB2LILRB3LPLSQSTM1SREBF1
Complex memberships
ANGPTL3-ANGPTL8 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 ANGPTL8 is required for the metabolic transition between fasting and refeeding; knockout mice show reduced VLDL secretion and increased LPL activity in the fed state, with impaired fatty acid uptake specifically in adipose tissue but preserved uptake in heart, demonstrating a tissue-selective role in directing dietary TG to adipose storage. Angptl8 knockout mouse model, LPL activity assays, VLDL secretion assays, tissue lipid uptake measurements Proceedings of the National Academy of Sciences of the United States of America High 24043787
2012 ANGPTL8 (RIFL) is an insulin-regulated gene whose knockdown during adipogenesis reduces adipocyte triglyceride content by ~35%, and whose expression is induced >100-fold during adipogenesis and by refeeding in fat and liver, indicating a prolipogenic function. siRNA knockdown in 3T3-L1 adipocytes, triglyceride content measurement, Angptl8-null mouse model, transcriptional profiling American journal of physiology. Endocrinology and metabolism High 22569073
2017 ANGPTL8 possesses a functional LPL inhibitory motif but requires ANGPTL3 expression to inhibit LPL and elevate plasma TG; ANGPTL3 activity is not required for its ability to activate ANGPTL8, and the ANGPTL3-ANGPTL8 complex is far more efficacious at raising TG than ANGPTL3 alone. An antibody to the C-terminus of ANGPTL8 blocks LPL inhibition without disrupting the complex. Co-expression in mouse models, mutated ANGPTL3 (LPL-inhibitory activity ablated), monoclonal antibody blockade, in vivo TG measurements Journal of lipid research High 28413163
2017 ANGPTL8 physically binds ANGPTL3 (detected by Co-IP and NanoBiT split-luciferase); the ANGPTL3-ANGPTL8 complex dramatically increases ANGPTL3's ability to bind LPL compared to either protein alone, and co-expression with ANGPTL3 greatly enhances ANGPTL8 secretion. Adenoviral overexpression of ANGPTL3 raises plasma TG only in the presence of ANGPTL8. Co-immunoprecipitation, NanoBiT split-luciferase protein interaction assay, lipase activity assays, adenovirus injection in Angptl8-null mice Molecular metabolism High 29031715
2017 Intracellular ANGPTL8 functions as a negative feedback regulator of TNFα-triggered NF-κB activation by facilitating the interaction of IKKγ with p62/SQSTM1 to promote selective autophagic degradation of IKKγ; N-terminal domain-mediated self-oligomerization of ANGPTL8 is essential for this activity. Knockdown/knockout of ANGPTL8 in cell lines, Co-IP, autophagic flux assays, domain mutagenesis, LPS-injected mouse model Nature communications High 29255244
2020 Hepatic ANGPTL8 acts endocrinally (with ANGPTL3) to inhibit intravascular LPL in oxidative tissues, whereas adipose-tissue ANGPTL8 acts autocrine/paracrinely to inhibit ANGPTL4 and thereby enhance local LPL activity; co-expression of ANGPTL8 with ANGPTL4 in cultured cells reduces ANGPTL4 secretion and ANGPTL4-mediated LPL inhibition. Liver-specific and adipose-specific Angptl8 knockout mice, plasma TG and LPL activity assays, cell-based ANGPTL4 secretion assays JCI insight High 32730227
2019 ANGPTL8 resets diurnal rhythms of hepatic clock and metabolic genes in mice through signaling via membrane receptor PirB (LILRB), phosphorylation of downstream kinases and transcription factors, and transient activation of the clock gene Per1; inhibition of ANGPTL8 signaling partially blocks food-entrained resetting of the liver clock. Angptl8 knockout and overexpression in mice, PirB blocking, gene expression profiling, circadian rhythm analysis Nature communications High 31388006
2014 ANGPTL8 does not control pancreatic beta cell expansion; Angptl8-null mice undergo normal beta cell expansion in response to insulin resistance from high-fat diet or S961 administration, and liver overexpression of ANGPTL8 doubles plasma TG but does not alter beta cell expansion or glucose metabolism. Angptl8 knockout mice, high-fat diet and S961 insulin resistance models, beta cell quantification, hepatic overexpression Cell High 25417115
2015 A monoclonal antibody targeting the EIQVEE epitope of ANGPTL8 (Lipasin) lowers serum TG in mice; Lipasin-deficient mice show elevated postprandial LPL activity specifically in heart and skeletal muscle but not white adipose tissue, indicating lipasin suppresses LPL in cardiac/skeletal muscle to redirect circulating TG to adipose tissue in the fed state. Monoclonal antibody generation and injection, Lipasin-deficient mouse model, tissue LPL activity assays, fed/fasted TG measurements Scientific reports High 26687026
2018 HCC-associated protein TD26 (ANGPTL8) interacts via its C-terminus (aa 121–198) with the truncated nuclear form of SREBP1 (nSREBP1) but not full-length SREBP1, blocking AMPK-mediated inhibition of SREBP1 activity, thereby increasing lipogenesis and promoting tumor cell proliferation. Co-immunoprecipitation, domain truncation mapping, AMPK inhibition assays, metabolomics, in vitro and in vivo tumor growth assays Hepatology High 29663480
2022 ANGPTL8 accelerates hepatic stellate cell activation and liver fibrosis by interacting with the LILRB2 receptor to induce ERK signaling and upregulate profibrotic gene expression; liver-derived ANGPTL8 was confirmed as the active source by AAV8-mediated liver-specific restoration in KO mice. ANGPTL8 KO mice (HFD, HFHC, CCL4 models), AAV8 liver restoration, Co-IP, protein array, RNA-seq, histology Journal of advanced research High 36031141
2022 ANGPTL8 serves as a negative regulator of pathological cardiac hypertrophy by directly binding to LILRB3 (PirB) and inhibiting Akt/GSK3β activation; ANGPTL8 deficiency accelerates Ang II- or TAC-induced cardiac hypertrophy, while recombinant ANGPTL8 protein attenuates cardiomyocyte enlargement in vitro. ANGPTL8 KO mice (Ang II and TAC models), recombinant protein treatment in primary cardiomyocytes, RNA-seq, immunoprecipitation-mass spectrometry, siRNA-LILRB3 and anti-LILRB3 blocking Cell death & disease High 35851270
2018 ANGPTL8 antisense oligonucleotide treatment in high-fat-fed rats increases postprandial TG uptake in white adipose tissue, prevents hepatic steatosis, inhibits PKCε activation, and rescues hepatic insulin resistance, positioning adipose-tissue LPL disinhibition as the mechanistic basis. ASO knockdown in rats and mice, hyperinsulinemic-euglycaemic clamps, tissue lipid content, PKCε activation, Akt phosphorylation assays, meal tolerance tests Diabetologia High 29497783
2017 ANGPTL8 knockdown in 3T3-L1 adipocytes enhances intracellular lipolysis (increased NEFA release) and upregulates Angptl4, Leptin, Cpt1a, Cpt1b, and Pgc-1α; it also alters cellular phospholipid composition (reduces alkyl-PCs and PE plasmalogens), indicating that ANGPTL8 acts to suppress intracellular lipolysis and regulate the cellular lipidome. Lentiviral shRNA knockdown in 3T3-L1 adipocytes, lipolysis assays, lipidomics, gene expression analysis Chemistry and physics of lipids Medium 28528274
2016 ANGPTL8 overexpression in HepG2 cells enhances insulin-stimulated Akt-GSK3β and Akt-FoxO1 phosphorylation regardless of insulin resistance status; knockout of ANGPTL8 attenuates these pathways specifically under insulin resistance conditions, suggesting ANGPTL8 activates insulin signaling via the PI3K/Akt axis. TALEN-mediated KO and stable overexpression in HepG2 cells, western blot of Akt/GSK3β/FoxO1 phosphorylation under normal and insulin-resistant conditions Experimental cell research Medium 26387753
2020 ANGPTL8 enhances insulin sensitivity by directly activating AKT phosphorylation in the insulin-mediated PI3K/AKT signaling pathway; Ser94 and Thr98 on ANGPTL8 are the key residues required for AKT activation, identified by point mutation and fragment truncation analysis. Hydrodynamic tail vein transfection in mice, siRNA knockdown and in vitro mRNA overexpression in primary hepatocytes, site-directed mutagenesis, western blot of AKT phosphorylation Gene Medium 32344005
2016 ANGPTL8 (RIFL) expression is suppressed by lipolytic stimuli (β-adrenergic agonist isoproterenol, adenylate cyclase activator forskolin) and modestly reduces TG content when knocked down; a >8-fold increase in ANGPTL8 expression is seen in WAT of ob/ob mice and ~80-fold after refeeding, consistent with its role as an insulin/refeeding-induced LPL regulator. Angptl8 KO mice, 3T3-L1 adipocyte knockdown, pharmacological stimulation, gene expression, TG content measurement Scientific reports (Dang et al.) Medium 27845381
2015 ANGPTL8 expression in hepatocytes is regulated by the LXR/SREBP-1 signaling pathway; LXR agonist T0901317, palmitic acid, and tunicamycin all upregulate ANGPTL8 expression, while AICAR (AMPK activator) suppresses LXR/SREBP-1-induced ANGPTL8 expression through PPARα phosphorylation. HepG2 cell pharmacological treatments, siRNA for SREBP-1, gene expression analysis, AICAR and PPARα inhibitor experiments Molecular and cellular endocrinology Medium 26254015
2020 Insulin acutely induces Angptl8 expression in liver and adipose tissue via the CCAAT/enhancer-binding protein (C/EBPβ) transcription factor; glucose further enhances adipose Angptl8 expression in the presence of insulin; AMPK activation antagonizes insulin-stimulated Angptl8 expression in hepatocytes and adipocytes. In vivo insulin clamp experiments in mice, primary hepatocyte and adipocyte cultures, C/EBPβ identification, luciferase reporter assays, AMPK pathway inhibition American journal of physiology. Endocrinology and metabolism Medium 32154742
2020 Transcriptional regulation of Angptl8 in the liver is mediated by HNF-1α/β binding to a defined site (-84/-68 bp) in the Angptl8 promoter; HNF-1α binding is confirmed by EMSA and ChIP, and HNF-1α levels increase rapidly after refeeding in parallel with Angptl8 expression; insulin-induced Angptl8 upregulation is completely abolished by HNF-1 knockdown. Promoter deletion/mutation analysis, luciferase reporter assay, EMSA, ChIP, HNF-1 siRNA in hepatoma cells and primary hepatocytes Scientific reports High 32561878
2017 MicroRNA-221-3p targets the ANGPTL8 mRNA 3'UTR to reduce ANGPTL8 protein expression in adipocytes; inflammatory macrophage-conditioned medium induces miR-221-3p which suppresses ANGPTL8 expression, linking adipose inflammation to reduced ANGPTL8 levels. miR-221-3p mimic/inhibitor transfection in human adipocytes, 3'UTR luciferase reporter assay, subcutaneous adipose tissue biopsies from lean to obese subjects The Journal of clinical endocrinology and metabolism Medium 28938482
2022 The ANGPTL3-ANGPTL8 complex targets both LPL and endothelial lipase (EL/LIPG) in humans; genetic mimicry analysis shows the R59W substitution in ANGPTL8 more strongly affects EL inhibition than LPL inhibition, while a rare protein-truncating ANGPTL8 variant shows the complex to be LPL-specific. Human genetic mimicry analysis using UK Biobank (>110,000 individuals) and 11 European population cohorts, variant-specific metabolite profiling Journal of lipid research Medium 36372100
2024 ANGPTL8 in the diabetic brain is secreted by neurons into the hippocampus and acts via its receptor PirB (LILRB) on both neurons and microglia; in neurons it downregulates synaptic and axonal markers, in microglia it upregulates proinflammatory cytokines, collectively causing neuroinflammation and synaptic loss; neuron-specific Angptl8 KO prevents these effects. Neuron-specific Angptl8 KO mice, PirB-/- mice, recombinant ANGPTL8 protein treatment, Barnes Maze and novel object recognition, synaptic marker assays, cytokine measurement Journal of neuroinflammation Medium 39095838
2018 ANGPTL8 knockdown in primary mouse subcutaneous preadipocytes impedes adipocyte differentiation, reduces TG accumulation, attenuates isoproterenol-stimulated lipolysis, and reduces early expression of adipogenic genes (PPARγ) and insulin signaling genes, as well as decreasing insulin-stimulated Akt phosphorylation at early differentiation. siRNA knockdown, RNA-seq at multiple differentiation time points, Akt phosphorylation western blot, lipolysis assays in primary preadipocytes Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 38272177
2024 ANGPTL8 deficiency attenuates LPS-induced liver injury by activating the PGC1α/PPARα pathway to improve fatty acid oxidation; LPS promotes ANGPTL8 expression via TNF-α, and Angptl8 KO reduces hepatic lipid accumulation and lipid peroxidation, improving survival in septic mice. Angptl8 KO mice, LPS-induced liver injury model, TNF-α pathway inhibition, PGC1α/PPARα pathway analysis, survival studies Journal of lipid research Medium 39019343
2016 ANGPTL8 siRNA knockdown in trophoblast cells reduces JNK signaling activation under insulin-resistant conditions, ameliorating insulin resistance; JNK antagonists attenuate and JNK agonists aggravate the effect of ANGPTL8 knockdown, placing ANGPTL8 upstream of JNK in insulin resistance signaling. siRNA knockdown in HTR-8/SVneo trophoblast cells, JNK pathway pharmacological modulation, glucose uptake assay Frontiers in endocrinology Low 34163433
2022 ANGPTL8 promotes differentiation of mesenchymal stem cells into adipocytes by inhibiting the Wnt/β-catenin pathway and upregulating PPARγ and C/EBPα; this was confirmed using Wnt/β-catenin activators (LiCl and CHIR99021) that reverse ANGPTL8-mediated differentiation promotion. ANGPTL8 KO mice, MSC isolation and differentiation assays, Wnt/β-catenin pathway activators, PPARγ and C/EBPα mRNA expression Frontiers in endocrinology Medium 36034432
2024 ZNF638 transcriptionally represses Angptl8 in adipose tissue by recruiting HDAC1 for histone deacetylation; adipose-specific ZNF638 knockout elevates Angptl8 and raises serum TG after refeeding in female mice, and neutralizing circulating ANGPTL8 abolishes this TG elevation, placing ANGPTL8 downstream of ZNF638 in a sexually dimorphic, estrogen-dependent pathway. Adipose-specific ZNF638 KO mice, adenoviral overexpression, ANGPTL8 neutralizing antibody, RNA-seq, ChIP-based histone deacetylation assay Metabolism: clinical and experimental Medium 38211696
2023 ANGPTL8 promotes HCC cell proliferation by activating LILRB2/PIRB to regulate the ROS/ERK pathway and upregulate autophagy in hepatocytes; simultaneously, the ANGPTL8-LILRB2/PIRB interaction polarizes macrophages to an immunosuppressive M2 phenotype and recruits immunosuppressive T cells. ANGPTL8 KO in DEN-induced mouse HCC, in vitro proliferation assays, flow cytometry, RNA-seq, immunohistochemistry, western blot for ERK/autophagy markers Oncogenesis Medium 37188659
2022 Sebacic acid (a royal jelly fatty acid) downregulates ANGPTL8 expression in HepG2 cells by reducing HNF4α protein levels and its binding to the ANGPTL8 promoter; siRNA knockdown of HNF4α suppresses ANGPTL8 mRNA, identifying HNF4α as a transcriptional activator of ANGPTL8. Reporter assay for ANGPTL8 promoter, HNF4α binding site identification, siRNA knockdown of HNF4α, ChIP-like promoter binding assay in HepG2 cells Bioscience, biotechnology, and biochemistry Medium 35325025
2016 ANGPTL8 is localized to the cytoplasm of adipocytes co-localizing with perilipin-1, and its mRNA is also present in endothelial cells of visceral adipose tissue; this subcellular localization is consistent with both intracellular metabolic function and a paracrine/endocrine secretory role. Immunocytochemistry, Western blotting, in situ hybridization, RT-PCR in human visceral adipose tissue biopsies from obese and non-obese subjects Journal of clinical medicine Low 32069954
2018 GLP-1 receptor agonists (exendin-4, liraglutide) upregulate ANGPTL8 expression and secretion in HepG2 cells via the PI3K/Akt pathway in a GLP-1 receptor-dependent manner; effects are blocked by the GLP-1R antagonist exendin (9-39) and the PI3K inhibitor LY294002. HepG2 cell pharmacological treatment with GLP-1R agonists/antagonists and PI3K inhibitor, ANGPTL8 expression and secretion measurement Peptides Medium 30003931

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 281 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 266 22569073
2014 ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell 178 25417115
2017 ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. Journal of lipid research 177 28413163
2017 ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Molecular metabolism 157 29031715
2017 ANGPTL8 negatively regulates NF-κB activation by facilitating selective autophagic degradation of IKKγ. Nature communications 94 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 78 33011191
2022 ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways. Journal of advanced research 72 36031141
2020 ANGPTL8 has both endocrine and autocrine effects on substrate utilization. JCI insight 72 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 67 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 64 29719529
2015 Angiopoietin-like protein 8 (ANGPTL8)/betatrophin overexpression does not increase beta cell proliferation in mice. Diabetologia 61 25917759
2015 ANGPTL8/betatrophin alleviates insulin resistance via the Akt-GSK3β or Akt-FoxO1 pathway in HepG2 cells. Experimental cell research 59 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 Increased plasma and adipose tissue levels of ANGPTL8/Betatrophin and ANGPTL4 in people with hypertension. Lipids in health and disease 46 29490644
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.) 46 29663480
2021 ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease. PLoS genetics 38 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
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
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 22 32154742
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
2017 Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition. Chemistry and physics of lipids 20 28528274
2021 Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8. The Journal of clinical endocrinology and metabolism 19 33619548
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
2020 Predictive values of ANGPTL8 on risk of all-cause mortality in diabetic patients: results from the REACTION Study. Cardiovascular diabetology 18 32746907
2017 Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus. G3 (Bethesda, Md.) 18 28754724
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
2016 The Rise and the Fall of Betatrophin/ANGPTL8 as an Inducer of β-Cell Proliferation. Journal of diabetes research 17 27672665
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
2019 The Relationship between Circulating ANGPTL8/Betatrophin Concentrations and Adult Obesity: A Meta-Analysis. Disease markers 15 31772689
2016 ANGPTL8 reverses established adriamycin cardiomyopathy by stimulating adult cardiac progenitor cells. Oncotarget 15 27823982
2024 Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway. Journal of neuroinflammation 14 39095838
2021 Role of ANGPTL8 in NAFLD Improvement after Bariatric Surgery in Experimental and Human Obesity. International journal of molecular sciences 14 34884755
2018 A new way to regulate inflammation: selective autophagic degradation of IKKγ mediated by ANGPTL8. Cell stress 14 31225468
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 Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy. International journal of molecular sciences 11 37762544
2021 ANGPTL8 roles in proliferation, metabolic diseases, hypothyroidism, polycystic ovary syndrome, and signaling pathways. Molecular biology reports 11 33864588
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 Dual role of ANGPTL8 in promoting tumor cell proliferation and immune escape during hepatocarcinogenesis. Oncogenesis 10 37188659
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 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice. Clinical science (London, England : 1979) 9 37294581
2021 Association of ANGPTL8 and Resistin With Diabetic Nephropathy in Type 2 Diabetes Mellitus. Frontiers in endocrinology 9 34603198
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
2023 ANGPTL8 links inflammation and poor differentiation, which are characteristics of malignant renal cell carcinoma. Cancer science 8 36529524
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 ANGPTL8 deficiency attenuates lipopolysaccharide-induced liver injury by improving lipid metabolic dysregulation. Journal of lipid research 7 39019343
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
2021 Circulating ANGPTL8 levels and risk of kidney function decline: Results from the 4C Study. Cardiovascular diabetology 7 34167540
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
2024 Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice. iScience 6 39640567
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 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
2024 Relationship between serum levels of ANGPTL8, Apo C2, and human placental lactogen (hPL) in patients with gestational diabetes mellitus: Interaction of LPL regulators with hPL, a possible contributing factor to insulin resistance. Placenta 4 39700905