506-P: Regulation of ANGPTL3 by SEL1L-HRD1 ER-Associated Degradation

Abstract

Angiopoietin-like 3 (ANGPTL3) is a liver-derived circulating factor critical for systemic lipid metabolism via the inhibition of lipoprotein lipase (LPL). Loss-of-function mutations in ANGPTL3 in humans and mice reduce circulating levels of triglycerides. Here, we report the discovery of a novel mechanism regulating the biosynthesis and maturation of nascent ANGPTL3 in the endoplasmic reticulum (ER). Mice with acute or chronic liver-specific deletion of SEL1L-HRD1, the most conserved branch of mammalian endoplasmic reticulum (ER)-associated degradation (ERAD) machinery, exhibit significantly lower levels of triglyceride and cholesterol in the serum with reduced weights of both epididymal and inguinal white adipose tissues (WAT). Various proteomics screenings have identified ANGPTL3 as a possible link between SEL1L-HRD1 ERAD and hypolipidemia. Indeed, ANGPTL3 is a bona fide endogenous substrate of SEL1L-HRD1 ERAD in the liver and in the absence of ERAD, ANGPTL3 protein is retained in the ER, forming high-molecular weight aggregates. This abnormal ER retention of ANGPTL3 accounts for a reduced circulating level of ANGPTL3, therefore contributing to hypolipidemia in ERAD-deficient mice. Together, this study not only uncovers a novel regulator for ANGPTL3 and novel targets in the treatment of hyperlipidemia in obesity and diabetes. Disclosure L.Zhou: None. L.Lin: None. S.Sun: None. L.Qi: None.