Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism (PubMed:
11788823, PubMed:
12909640, PubMed:
23661675, PubMed:
25495645). Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N- terminal domain, and is not inhibited by GPIHBP1 (PubMed:
12097324, PubMed:
19318355, PubMed:
20581395). Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids (PubMed:
17110602, PubMed:
19028676). Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol (PubMed:
12565906). Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).
