The role and mode of action of apolipoproteins CIII and AV: synergistic actors in triglyceride metabolism?

Abstract

Apolipoprotein (apo)CIII and apoAV play an important role in triglyceride metabolism as evidenced by the unambiguous and opposing phenotypes of transgenic and knockout mouse models. In this review we discuss studies on the genetics, protein structure, and regulation of apoCIII and apoAV and compare their potential molecular mechanisms of action in triglyceride metabolism. We examine the hypothesis that apoCIII and apoAV synergistically affect triglyceride metabolism. It has now been firmly established that variation in plasma triglyceride levels in a wide range of human populations is strongly associated with genetic variation at the chromosomal locus encoding both the APOC3 and APOA5 genes, the APOA1/C3/A4/A5 gene cluster. The close physical linkage of these genes and the frequent concurrence of genetic variants, however, complicate the assignment of specific metabolic defects to specific polymorphisms. Recent insight into the regulation of APOC3 and APOA5 gene expression and structural modeling studies on the apoAV protein have provided novel clues for the potential molecular mechanisms responsible for the effects of apoCIII and apoAV on triglyceride metabolism. Hypertriglyceridemia is a major independent risk factor in the development of cardiovascular disease. Moreover, triglyceride-derived fatty acids are thought to play a key role in the development and progression of the metabolic syndrome. As modulators of triglyceride metabolism, apoCIII and apoAV are key players and potential therapeutic targets. However, little is known of their molecular mechanism and potential cooperativity. Rational therapeutic application will require the filling of this hiatus in our knowledge.