ANGPTL8

Summary: Hormone activity (IBA). ANGPTL8 is a circulating hepatokine that acts on LPL in distant tissues; accepted.

Reason: [PMID:23150577 "ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans."] Hepatic ANGPTL8 acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues [PMID:32730227 "Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4."].

Summary: Hormone activity (IDA). ANGPTL8 is a circulating hepatokine that acts on LPL in distant tissues; accepted.

Reason: [PMID:23150577 "ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans."] Hepatic ANGPTL8 acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues [PMID:32730227 "Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4."].

Summary: Protein binding (IPI) with RCHY1, from a proteome-scale liver interactome. Uninformative; removed.

Reason: A high-throughput yeast two-hybrid hit between a secreted protein and an intracellular E3 ligase, with no follow-up. Generic protein binding is not informative; ANGPTL8's functional partner is ANGPTL3.

Summary: Extracellular region (IBA). ANGPTL8 is secreted and circulates; accepted.

Reason: [PMID:23150577 "ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans."]

Summary: Extracellular region (IDA). ANGPTL8 is secreted and circulates; accepted.

Reason: [PMID:23150577 "ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans."]

Summary: Extracellular region (IEA). ANGPTL8 is secreted and circulates; accepted.

Reason: [PMID:23150577 "ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans."]

Summary: Extracellular region (TAS). ANGPTL8 is secreted and circulates; accepted.

Reason: [PMID:23150577 "ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans."]

Summary: Lipid metabolic process (IEA). Correct, general; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."].

Summary: Lipid metabolic process (ISS). Correct, general; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."].

Summary: Signal transduction (IEA, inferred from hormone activity). ANGPTL8 does signal through the PirB/LILRB receptors in several tissues, but this is secondary to its LPL role; kept as non-core.

Reason: The mapping follows automatically from hormone activity, but independent groups support it: ANGPTL8 resets the liver clock through the membrane receptor PirB [PMID:31388006 "Mechanistically, the resetting function of Angptl8 is dependent on the signal relay of the membrane receptor PirB, phosphorylation of kinases and transcriptional factors, and consequently transient activation of the central clock gene Per1."], binds LILRB3 in cardiomyocytes [PMID:35851270 "Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening."], and acts through PirB in the hippocampus [PMID:39095838 "In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage."]. These receptor effects are tissue- and disease-specific. ANGPTL8's best-established physiological role remains LPL inhibition with ANGPTL3 [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."].

Summary: Positive regulation of protein processing (IDA, acts_upstream_of_or_within). ANGPTL8 increases release of the N-terminal ANGPTL3 fragment; kept as non-core.

Reason: [PMID:23150577 "In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3."] In humans, the ANGPTL8 R59W variant is associated with more cleaved ANGPTL3 in plasma [PMID:27117576 "The variant allele was associated with increased levels of cleaved ANGPTL3."]. This is an effect on ANGPTL3 maturation that accompanies complex formation, not ANGPTL8's main activity, which is LPL inhibition within the complex.

Summary: Regulation of lipid metabolic process (IBA). ANGPTL8 regulates triglyceride partitioning via LPL; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. [PMID:32730227 "Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4."]

Summary: Regulation of lipid metabolic process (IDA). ANGPTL8 regulates triglyceride partitioning via LPL; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. [PMID:32730227 "Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4."]

Summary: Regulation of lipid metabolic process (IEA). ANGPTL8 regulates triglyceride partitioning via LPL; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. [PMID:32730227 "Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4."]

Summary: NOT type B pancreatic cell proliferation (IDA). The paper refutes the betatrophin hypothesis; the negated annotation is correct and accepted.

Reason: [PMID:25417115 "ANGPTL8/betatrophin does not control pancreatic beta cell expansion."] Angptl8 knockout mice have low triglycerides but normal glucose homeostasis [PMID:25417115 "revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis"]. The original betatrophin report was retracted (UniProt CAUTION, PMID:28038792), so the NOT annotation records the settled result.

Summary: Regulation of lipoprotein metabolic process (IBA). ANGPTL8 controls LPL-mediated lipoprotein triglyceride hydrolysis; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."].

Summary: Regulation of lipoprotein metabolic process (IEA). ANGPTL8 controls LPL-mediated lipoprotein triglyceride hydrolysis; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."].

Summary: Regulation of lipoprotein metabolic process (IMP). ANGPTL8 controls LPL-mediated lipoprotein triglyceride hydrolysis; accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."].

Summary: Triglyceride homeostasis (IBA). Accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. Without ANGPTL3, ANGPTL8 cannot raise triglycerides [PMID:23150577 "Consistent with this scenario, expression of ANGPTL8 in Angptl3(-/-) mice failed to promote hypertriglyceridemia."]; Angptl8 knockout mice have markedly lower triglycerides [PMID:25417115 "revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis"].

Summary: Triglyceride homeostasis (IDA). Accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. Without ANGPTL3, ANGPTL8 cannot raise triglycerides [PMID:23150577 "Consistent with this scenario, expression of ANGPTL8 in Angptl3(-/-) mice failed to promote hypertriglyceridemia."]; Angptl8 knockout mice have markedly lower triglycerides [PMID:25417115 "revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis"].

Summary: Triglyceride homeostasis (IEA). Accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. Without ANGPTL3, ANGPTL8 cannot raise triglycerides [PMID:23150577 "Consistent with this scenario, expression of ANGPTL8 in Angptl3(-/-) mice failed to promote hypertriglyceridemia."]; Angptl8 knockout mice have markedly lower triglycerides [PMID:25417115 "revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis"].

Summary: Triglyceride homeostasis (IGI). Accepted.

Reason: ANGPTL8 forms a complex with ANGPTL3 that inhibits lipoprotein lipase far more strongly than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."], and coexpression of the two raises plasma triglycerides [PMID:23150577 "Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3."]. Without ANGPTL3, ANGPTL8 cannot raise triglycerides [PMID:23150577 "Consistent with this scenario, expression of ANGPTL8 in Angptl3(-/-) mice failed to promote hypertriglyceridemia."]; Angptl8 knockout mice have markedly lower triglycerides [PMID:25417115 "revealed profound reduction of triglyceride levels, but no abnormalities in glucose homeostasis"].

Summary: Proposed. ANGPTL8 supplies the LPL-inhibitory motif of the ANGPTL3-ANGPTL8 complex, which inhibits lipoprotein lipase.

Reason: The ANGPTL3-ANGPTL8 complex is a far stronger LPL inhibitor than either protein alone [PMID:29031715 "Importantly, ANGPTL3-ANGPTL8 complexes had a dramatically increased ability to inhibit LPL compared to either protein alone."]. ANGPTL8 does part of the work: it carries a functional LPL inhibitory motif [PMID:28413163 "ANGPTL8 has a functional LPL inhibitory motif, but only inhibits LPL and increases plasma TG levels in mice in the presence of ANGPTL3"], and the major inhibitory activity of the complex derives from it [PMID:28413163 "suggesting the major inhibitory activity of this complex derives from ANGPTL8"]. Because ANGPTL8 alone is inactive, contributes_to is the right qualifier. Comparator check: ANGPTL3 and ANGPTL4, the other LPL-inhibiting angiopoietin-like proteins, both carry GO:0055102 in GOA. No current ANGPTL8 annotation is an ancestor or descendant of this term.