Abstract

Acylation Stimulating Protein (ASP) is a potent stimulator of triglyceride synthesis (TGS) and glucose transport in human skin fibroblasts, muscle cells and, particularly, adipocytes. It is produced through the interaction of three proteins of the alternate complement pathway of the immune system, C3, factor B and adipsin. These three proteins are secreted from adipose tissue, and interact in plasma to produce C3a, which is then desarginated at the C-terminal to form ASP. ASP then acts back on adipose tissue in an autocrine fashion. ASP production is stimulated by dietary fat, in the form of chylomicrons, and thereby increases the efficiency of uptake of dietary fat in much the same manner as insulin increases glucose uptake. Although ASP and C3a differ by only one amino acid, ASP does not bind to the C3a receptor, and is generally thought to be inactive in the immune system. Since initial binding studies indicated the existence of a specific ASP receptor, studies were undertaken to identify the ASP receptor. The results demonstrate that C5L2, originally cloned as an orphan G protein coupled receptor, is a functional ASP receptor. C5L2 binds ASP with high affinity and can mediate the TGS stimulatory function of ASP when transfected into cells that are not normally responsive to ASP. Furthermore, interfering with the expression of C5L2 in normally responsive cells diminishes the ASP effect on TGS in these cells. C5L2 is also expressed to a high degree in adipose tissue. Previous studies in both humans and mice have provided evidence of the physiological importance of ASP in the metabolism of dietary fat. Thus the identification of the ASP receptor furthers our knowledge of a regulatory pathway that may play a role in the development of obesity, and associated cardiovascular diseases and diabetes.