The human body obtains energy through the breakdown of fatty acids, which are often stored as a complex called triacylglycerol. In order to initiate the production of TAG, the enzyme Glycerol-3-phosphate Acyltransferase (GPAT) must make an ester bond connecting the glycerol to a long-chain fatty acyl-CoA to form lysophosphatidic acid (LPA). This step of the TAG biosynthesis pathway is peculiar because GPAT exists as four different isoforms, which all catalyze the formation of LPA. The reason why the four isoenzymes are necessary is unknown. GPAT1 and GPAT4 isoforms are the most present isoforms in the liver. GPAT1 expression increases when carbohydrate and insulin concentrations in the body are high. GPAT4 is responsible for the rest of the activity in the liver and is linked to TAG synthesis. Because the transcription factor, SREBP1c, up-regulates GPAT1 as well as enzymes that take part in de novo synthesis of fatty acids, the authors believe that the function of GPAT1 is linked to de novo processes and that GPAT4 is not.
The authors began by showing that cultured liver cells from control and Gpat1-/- or Gpat4-/- knockout mice retain GPAT specific activity (as they would when inside the mouse). Using radiolabeled palmitate they found that both GPAT1 and GPAT4 incorporate exogenous fatty acids into TAG. Then using radiolabeled acetate and in vivo studies, they found that GPAT1, but not GPAT4, is required to incorporate de novo synthesized fatty acids into TAG. Also, by using radiolabeled palmitate incorporated into acid-soluble metabolites, and in vivo studies, they found that the absence of GPAT1, but not GPAT4 increased fatty acid oxidation of both de novo and exogenous fatty acids. This is consistent with the idea that GPAT1 competes with a mitochondrial protein (CPT1) for acyl-CoA, therefore decreasing the amount of fatty acid brought to the mitochondria for oxidation. This study clearly shows that GPAT1 and not GPAT4, regulates de novo TAG synthesis and fatty acid oxidation. The absence of GPAT1 is shown to protect mice from high fat diet, fatty livers, and insulin resistance, which make it a good possible target for diabetes, hyperglycemia treatments, and obesity.
Paper: Glycerol-3-phosphate Acyltransferase (GPAT)-1, but Not GPAT4, Incorporates Newly Synthesized Fatty Acids into Triacylglycerol and Diminishes Fatty Acid Oxidation