Acyl-CoA synthesis, lipid metabolism and lipotoxicity

Abstract

Although the underlying causes of insulin resistance have not been completely delineated, in most analyses, a recurring theme is dysfunctional metabolism of fatty acids. Because the conversion of fatty acids to activated acyl-CoAs is the first and essential step in the metabolism of long-chain fatty acid metabolism, interest has grown in the synthesis of acyl-CoAs, their contribution to the formation of signaling molecules like ceramide and diacylglycerol, and their direct effects on cell function. In this review, we cover the evidence for the involvement of acyl-CoAs in what has been termed lipotoxicity, the regulation of the acyl-CoA synthetases, and the emerging functional roles of acyl-CoAs in the major tissues that contribute to insulin resistance and lipotoxicity, adipose, liver, heart and pancreas.

Fig. 1. Palmitate (16:0) is poorly incorporated into triacylglycerol and cardiolipin

Palmitic acid (16:0) is activated by an acyl-CoA synthetase and esterified to glycerol-3-phosphate to produce 16:0-LPA. Addition of a second 16:0-CoA produces di-16:0-PA, which is a precursor for the formation of PG and cardiolipin. The di-16:0-PA can also be hydrolyzed to form a DAG which is a precursor for the synthesis of triacylglycerol; however, 16:0-CoA is a poor substrate for DGAT and di-16:0-phosphatidylglycerol is a poor substrate for cardiolipin synthase (gray bars). ACBP, acyl-CoA binding protein; BSA, bovine serum albumin; CDP, cytidine diphosphate; CLS, cardiolipin synthase; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; G3P, glycerol-3-phosphate; FABP, fatty acid binding protein; LPA, lysophosphatidic acid; PA, phosphatidic acid; PG, phosphatidylglycerol; PI, phosphatidylinositol; TAG, triacylglycerol