Role and mechanism of the action of angiopoietin-like protein ANGPTL4 in plasma lipid metabolism

Triglycerides are carried in the bloodstream as the components of very low-density lipoproteins and chylomicrons. These circulating triglycerides are primarily hydrolyzed in muscle and adipose tissue by the enzyme lipoprotein lipase (LPL). The activity of LPL is regulated by numerous mechanisms, including by three members of the angiopoietin-like protein family: ANGPTL3, ANGPTL4, and ANGPTL8. In this review, we discuss the recent literature concerning the role and mechanism of action of ANGPTL4 in lipid metabolism. ANGPTL4 is a fasting- and lipid-induced factor secreted by numerous cells, including adipocytes, hepatocytes, (cardio)myocytes, and macrophages. In adipocytes, ANGPTL4 mediates the fasting-induced repression of LPL activity by promoting the unfolding of LPL, leading to the cleavage and subsequent degradation of LPL. The inhibition of LPL by ANGPTL4 is opposed by ANGPTL8, which keeps the LPL active after feeding. In macrophages and (cardio)myocytes, ANGPTL4 functions as a lipid-inducible feedback regulator of LPL-mediated lipid uptake. In comparison, in hepatocytes, ANGPTL4 functions as a local inhibitor of hepatic lipase and possibly as an endocrine inhibitor of LPL in extra-hepatic tissues. At the genetic level, loss-of-function mutations in ANGPTL4 are associated with lower plasma triglycerides and higher plasma HDL-C levels, and a reduced risk of coronary artery disease, suggesting that ANGPTL4 is a viable pharmacological target for reducing cardiovascular risk. Whole-body targeting of ANGPTL4 is contraindicated because of severe pathological complications, whereas liver-specific inactivation of ANGPTL4, either as monotherapy or coupled to anti-ANGPTL3 therapies might be a suitable strategy for lowering plasma triglycerides in selected patient groups. In conclusion, the tissue-specific targeting of ANGPTL4 appears to be a viable pharmacological approach to reduce circulating triglycerides.