Atypical angiopoietin-like protein that regulates ANGPTL3

Abstract

Angiopoietin-like proteins (ANGPTLs) play major roles in the trafficking and metabolism of lipids. Inactivation of ANGPTL3, a gene located in an intron of DOCK7, results in very low levels of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified another ANGPTL family member, ANGPTL8, which is located in the corresponding intron of DOCK6. A variant in this family member (rs2278426, R59W) was associated with lower plasma LDL-C and HDL-C levels in three populations. ANGPTL8 is expressed in liver and adipose tissue, and circulates in plasma of humans. Expression of ANGPTL8 was reduced by fasting and increased by refeeding in both mice and humans. To examine the functional relationship between the two ANGPTL family members, we expressed ANGPTL3 at physiological levels alone or together with ANGPTL8 in livers of mice. Plasma TAG level did not change in mice expressing ANGPTL3 alone, whereas coexpression with ANGPTL8 resulted in hypertriglyceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 coimmunoprecipitated with the N-terminal domain of ANGPTL3 in plasma of these mice. In cultured hepatocytes, ANGPTL8 expression increased the appearance of N-terminal ANGPTL3 in the medium, suggesting ANGPTL8 may activate ANGPTL3. Consistent with this scenario, expression of ANGPTL8 in Angptl3 −/− mice failed to promote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 that arose through duplication of an ancestral DOCK gene, regulates postprandial TAG and fatty acid metabolism by controlling activation of its progenitor, and perhaps other ANGPTLs. Inhibition of ANGPTL8 provides a new therapeutic strategy for reducing plasma lipoprotein levels.T he angiopoietin-like (ANGPTL) genes encode a family of secreted proteins with pleiotropic effects on vascular cells (1), lipid metabolism (2), and stem cell biology (3). The family members share a common architecture, comprising an extended N-terminal domain and a C-terminal fibrinogen-like domain. Genetic studies have revealed that two closely related family members, ANGPTL3 and ANGPTL4, play pivotal roles in the trafficking and metabolism of lipids and lipoproteins (4-7). Mutations that disrupt ANGPTL3 are associated with greatly reduced plasma levels of triacylglycerol (TAG) and cholesterol in mice (5) and in humans (4). Mice lacking ANGPTL4 also have markedly reduced levels of plasma TAG and cholesterol (8, 9), and sequence variations in ANGPTL4 are associated with lower plasma TAG levels in humans (7).TAG synthesized in the gut and liver are incorporated into chylomicrons and very low density lipoproteins (VLDL), respectively, and delivered to peripheral tissues where they interact with lipoprotein lipase (LPL). LPL hydrolyzes the TAGs, releasing fatty acids to the adjacent tissues. Other intravascular lipases, including hepatic lipase and endothelial lipase, further remodel lipoprotein particles. Several lines of evidence suggest that ANGPTL3 and ANGPTL4 contribute to the partitioning of TAGs among tissues (2). During fasting, ANGPTL4 levels increase in ad...

Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

“…Coexpression of ANGPTL8 and ANGPTL3 increased plasma TG levels more than 10-fold, suggesting that the two proteins act together (14). Consistent with this hypothesis, ANGPTL3 and ANGPTL8 can be coimmunoprecipitated in the plasma of mice or in the medium of cells expressing both proteins (14). These data suggest that ANGPTL8 acts together with ANGPTL3 to coordinate the trafficking of TGs to tissues in response to food intake.…”

“…Adenovirus-mediated hepatic overexpression of ANGPTL8 increases plasma TG levels in wild-type mice but not in mice lacking ANGPTL3 (12). Coexpression of ANGPTL8 and ANGPTL3 increased plasma TG levels more than 10-fold, suggesting that the two proteins act together (14). Consistent with this hypothesis, ANGPTL3 and ANGPTL8 can be coimmunoprecipitated in the plasma of mice or in the medium of cells expressing both proteins (14).…”

“…Previously, we (14) and others (11,12) showed that expression of ANGPTL8 is increased by food intake. To compare effects of fasting and refeeding on hepatic expression of Angptl8 with that of Angptl3 and Angptl4, we performed RNA-Seq on hepatic mRNA from wild-type mice.…”

“…ANGPTL8 is expressed at the highest levels in liver and adipose tissue, and is markedly up-regulated by feeding and suppressed by fasting (11,12,14). Adenovirus-mediated hepatic overexpression of ANGPTL8 increases plasma TG levels in wild-type mice but not in mice lacking ANGPTL3 (12).…”

“…Previously, we showed that ANGPTL8 [also known as TD26, RIFL (11), Lipasin (12), and Betatrophin (13)] acts together with ANGPTL3 (14). ANGPTL8 is expressed at the highest levels in liver and adipose tissue, and is markedly up-regulated by feeding and suppressed by fasting (11,12,14).…”