Regulation of Triglyceride Metabolism. II. Function of mitochondrial GPAT1 in the regulation of triacylglycerol biosynthesis and insulin action

Abstract

GPAT1, one of four known glycerol-3-phosphate acyltransferase isoforms, is located on the mitochondrial outer membrane, allowing reciprocal regulation with carnitine palmitoyltransferase-1. GPAT1 is upregulated transcriptionally by insulin and SREBP-1c and downregulated acutely by AMP-activated protein kinase, consistent with a role in triacylglycerol synthesis. Knockout and overexpression studies suggest that GPAT1 is critical for the development of hepatic steatosis and that steatosis initiated by overexpression of GPAT1 causes hepatic, and perhaps also peripheral, insulin resistance. Future questions include the function of GPAT1 in relation to the other GPAT isoforms and whether the lipid intermediates synthesized by GPAT and downstream enzymes in the pathway of glycerolipid biosynthesis participate in intracellular signaling pathways.

Fig. 1

Triacylglycerol synthesis is initiated by four glycerol-3-phosphate acyltransferases (GPATs). GPAT1 and -2 are located on the outer mitochondrial membrane where they compete with carnitine palmitoyltransferase (CPT1) for acyl-CoAs. GPAT3 and 4 are located on the endoplasmic reticulum (ER). The lysophosphatidic acid (LPA) that these GPAT isoforms synthesize are acylated by lysophosphatidic acid acyltransferases to form phosphatidic acid (PA), the precursor for phosphatidylinositol (PI), phosphatidylglycerol (PG), and cardiolipin (CL). Lipin converts PA to diacylglycerol (DAG), the precursor of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS), and diacylglycerol acyltransferase acylates DAG to form triacylglycerol (TAG). VLDL, very-low-density lipoprotein.