Abstract
Glycerol-3-phosphate acyltransferases (GPAT) catalyze the first step in the synthesis of glycerolipids and glycerophospholipids. Microsomal GPAT, the major GPAT activity, is encoded by at least two closely related genes, GPAT3 and GPAT4 (also known as AGPAT9 and 8, respectively). The physiological role of GPAT3 is poorly understood. GPAT3 mRNA was found to be abundantly expressed in small intestine which was confirmed by immunohistochemistry. The GPAT3 protein was highly enriched in enterocytes suggesting a potential role in intestinal lipid absorption. To further investigate this possibility, we generated Gpat3-deficient mice (Gpat3-/-). The Gpat3-/- mice were viable and fertile, and exhibited no obvious metabolic abnormalities on standard laboratory chow. As expected, Gpat3-/- mice had reduced intestinal GPAT activity compared to wild-type animals and when challenged with an oral lipid bolus, Gpat3-/- mice displayed attenuated plasma triglyceride excursion. Histological and biochemical analysis of the small intestine revealed dramatically increased lipid deposition in the intestinal mucosa of Gpat3-/- mice. Long chain acylcarnitine levels were elevated in the jejunum of Gpat3-/- suggesting a compensatory increase in mitochondrial fatty acid oxidation. Lipid flux studies performed in primary cultures of enterocytes derived from wild-type and Gpat3-/- mice reveal a defect in triacylglycerol trafficking suggesting a role for GPAT3 in the post-prandial secretion of lipid in the intestine. Finally, gene expression analysis revealed dysregulation of multiple genes involved in lipid absorption, chylomicron assembly, and secretion. Taken together, our results demonstrate a hitherto unappreciated role for GPAT3 in lipid absorption.
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