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Journal of Lipid Research, Vol. 49, 823-831, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Identification of a novel sn-glycerol-3-phosphate acyltransferase isoform, GPAT4, as the enzyme deficient in Agpat6^–/– mice

Cynthia A. Nagle^*, Laurent Vergnes, Hendrik DeJong^*, Shuli Wang^*, Tal M. Lewin^*, Karen Reue and Rosalind A. Coleman^1,*

^* Department of Nutrition, University of North Carolina, Chapel Hill, NC, 27599
Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095

Published, JLR Papers in Press, January 11, 2008.

¹ To whom correspondence should be addressed. e-mail: rcoleman{at}unc.edu

Elucidation of the metabolic pathways of triacylglycerol (TAG) synthesis is critical to the understanding of chronic metabolic disorders such as obesity, cardiovascular disease, and diabetes. sn-Glycerol-3-phosphate acyltransferase (GPAT) and sn-1-acylglycerol-3-phosphate acyltransferase (AGPAT) catalyze the first and second steps in de novo TAG synthesis. AGPAT6 is one of eight AGPAT isoforms identified through sequence homology, but the enzyme activity for AGPAT6 has not been confirmed. We found that in liver and brown adipose tissue from Agpat6-deficient (Agpat6^–/–) mice, N-ethylmaleimide (NEM)-sensitive GPAT specific activity was 65% lower than in tissues from wild-type mice, but AGPAT specific activity was similar. Overexpression of Agpat6 in Cos-7 cells increased an NEM-sensitive GPAT specific activity, but AGPAT specific activity was not increased. Agpat6 and Gpat1 overexpression in Cos-7 cells increased the incorporation of [¹⁴C]oleate into diacylglycerol (DAG) or into DAG and TAG, respectively, suggesting that the lysophosphatidic acid, phosphatidic acid, and DAG intermediates initiated by each of these isoforms lie in different cellular pools. Together, these data show that "Agpat6^–/– mice" are actually deficient in a novel NEM-sensitive GPAT, GPAT4, and indicate that the alterations in lipid metabolism in adipose tissue, liver, and mammary epithelium of these mice are attributable to the absence of GPAT4.

Supplementary key words triacylglycerol • phospholipid • lipodystrophy • acyl-coenzyme A • steatosis • sn-1-acylglycerol-3-phosphate O-acyltransferase-deficient mice

Abbreviations: AGPAT, sn-1-acylglycerol-3-phosphate O-acyltransferase; BAT, brown adipose tissue; DAG, diacylglycerol; GPAT, sn-glycerol-3-phosphate acyltransferase; LPA, lysophosphatidic acid; NEM, N-ethylmaleimide; PA, phosphatidic acid; TAG, triacylglycerol; WAT, white adipose tissue