New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk

The angiopoietin-like proteins (ANGPTLs), consisting of ANGPTL3, ANGPTL4, and ANGPTL8, have gained significant interest for their role as inhibitors of lipoprotein lipase (LPL) and for their potential as therapeutic targets for correcting dyslipidemia. This review provides an overview of the most relevant new insights on the connection between ANGPTLs, plasma lipids, and coronary artery disease.Carriers of loss-of-function variants in ANGPTL3 have a reduced risk of coronary artery disease and reduced plasma levels of triglycerides and LDL-C, while carriers of loss-of-function variants in ANGPTL4 have a reduced risk of coronary artery disease and reduced plasma levels of triglycerides and increased HDL-C. There is evidence that carrier status of ANGPTL4 loss-of-function variants may also influence risk of type 2 diabetes. ANGPTL3 is produced in liver and is released as a complex with ANGPTL8 to suppress LPL activity in fat and muscle tissue. ANGPTL4 is produced by numerous tissues and likely mainly functions as a locally released LPL inhibitor. Both proteins inactivate LPL by catalyzing the unfolding of the hydrolase domain in LPL and by promoting the cleavage of LPL. Antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 reduce plasma triglyceride and LDL-C levels in human volunteers and suppress atherosclerosis in mouse models.ANGPTL3/ANGPTL8 and ANGPTL4 together assure the appropriate distribution of plasma triglycerides across tissues during different physiological conditions. Large-scale genetic studies provide strong rationale for continued research efforts to pharmacologically inactivate ANGPTL3 and possibly ANGPTL4 to reduce plasma lipids and coronary artery disease risk.