Abstract

Acylation stimulating protein (ASP), a cleavage product of complement C3, is a potent stimulator of triacylglycerol synthesis in adipocytes. The three proteins necessary for ASP generation are complement C3, factor B and adipsin. In vivo studies have shown that there is an increased production of ASP in the micro-environment of adipose tissue after a meal and the level of ASP in the blood is substantially higher in obese individuals. Initial in vitro studies in our laboratory demonstrated that cultured differentiated adipocytes produce ASP and the postprandial component, chylomicrons (CHYLO), increased ASP production. Thus the present studies were undertaken firstly to identify the component of CHYLO responsible for the increase in ASP, and secondly to examine the CHYLO effects on the C3 (precursor), factor B and adipsin production. The results demonstrated that CHYLO stimulated ASP, C3, factor B and adipsin production in adipocytes. The stimulatory effects of CHYLO on ASP and C3 production were time- and concentration-dependant, with maximum levels at four to six hours of CHYLO stimulation. Transthyretin (TTR) was identified as a CHYLO component involved in the stimulatory effect. TTR and CHYLO transport retinyl ester/retinol, and it was determined that the TTR mediated retinoic acid transfer from CHYLO was involved in stimulating C3, factor B, and subsequently ASP, but not adipsin production. This CHYLO effect includes both de novo protein synthesis and secretion. While retinoic acid partly accounts for the stimulatory effect of CHYLO on C3, factor B and ASP production, we believe there are other factors that are relevant in regulating C3, factor B, adipsin, and ASP production. Taken together, these studies demonstrated that CHYLO is a novel physiological trigger that stimulates ASP production and the necessary proteins (C3, factor B, adipsin) required for ASP generation. This in turn can result in the direct stimulation of triacylglycerol storage in adipose tissue after a meal thereby enhancing the overall body fat stores. With the increase in obesity prevalence over the last decade, we believe that understanding the ASP pathway will allow us to better ascertain the physiological development of obesity and possible new drug targets in controlling it.