A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy

Abstract

Metabolic syndrome includes glucose intolerance and dyslipidemia, both of which are strong risk factors for developing diabetes and atherosclerotic cardiovascular diseases. Recently, multiple groups independently studied a previously uncharacterized gene, officially named C19orf80 (human) and Gm6484 (mouse), but more commonly known as RIFL, Angptl8, betatrophin and lipasin. Both exciting and conflicting results have been obtained, and significant controversy is ongoing. Accumulating evidence from genome wide association studies and mouse genetic studies convincingly shows that lipasin is involved in lipid regulation. However, the mechanism of action, the identity of transcription factors mediating its nutritional regulation, circulating levels, and relationship among lipasin, Angptl3 and Angptl4, remain elusive. Betatrophin represents a promising drug target for replenishing β-cell mass, but current results have not been conclusive regarding its potency and specificity. Here, we summarize the consensus and controversy regarding functions of lipasin/betatrophin based on currently available evidence.

Figure 1

Roles of lipasin (Angptl8) in regulating triglyceride metabolism and pancreatic beta-cell proliferation. Lipasin is secreted from the liver into the circulation, and is involved in triglyceride metabolism and in promoting pancreatic β-cell proliferation. Active as a dimmer, LPL binds to both HSPG and GPIHPB1 on the surface of capillary microvascular endothelial cells. LPL hydrolyzes TAG in chylomicrons and VLDL, yielding FFAs, which are then taken up by peripheral tissues, including fat, muscle and heart. Both Angptl3 and Angptl4 need to be cleaved to release functional N-termini to inhibit LPL, disrupting dimer formation either reversibly or irreversibly, respectively. Lipasin likely inhibits LPL directly or indirectly by promoting Angptl3 cleavage. Food intake dramatically induces the expression of lipasin, whereas fasting induces Angptl4. Dotted lines denote homologous regions. Angptl3, angiopoietin-like 3; Angptl4, angiopoietin-like 4; EC, endothelial cell; GPIHBP1, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1; FFA, free fatty acid; HSPG, heparan sulfate proteoglycans; LPL, lipoprotein lipase; TAG, triglyceride; VLDL, very low-density lipoprotein.

Figure 2

Expression levels of betatrophin, Angptl4 and Angptl3 in the mouse model of insulin resistance induced by the insulin receptor antagonist S961. A) Normalized and B) absolute expression levels of betatrophin, Angptl4 and Angptl3 in the liver of the mouse model of insulin resistance induced by the insulin receptor antagonist S961. The microarray data was obtained from the Gene Expression Omnibus with the accession number GSE45694. The gene symbol in the microarray dataset was Gm6484 (also known as Angptl8). Con, control; IR, insulin resistant.