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J. Biol. Chem., Vol. 283, Issue 15, 10048-10057, April 11, 2008

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AGPAT6 Is a Novel Microsomal Glycerol-3-phosphate Acyltransferase^*

Yan Qun Chen, Ming-Shang Kuo, Shuyu Li, Hai H. Bui, David A. Peake, Philip E. Sanders, Stefan J. Thibodeaux, Shaoyou Chu, Yue-Wei Qian, Yang Zhao, David S. Bredt, David E. Moller, Robert J. Konrad, Anne P. Beigneux, Stephen G. Young, and Guoqing Cao¹

From the Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285 and the Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095

AGPAT6 is a member of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family that appears to be important in triglyceride biosynthesis in several tissues, but the precise biochemical function of the enzyme is unknown. In the current study, we show that AGPAT6 is a microsomal glycerol-3-phosphate acyltransferase (GPAT). Membranes from HEK293 cells overexpressing human AGPAT6 had higher levels of GPAT activity. Substrate specificity studies suggested that AGPAT6 was active against both saturated and unsaturated long-chain fatty acyl-CoAs. Both glycerol 3-phosphate and fatty acyl-CoA increased the GPAT activity, and the activity was sensitive to N-ethylmaleimide, a sulfhydryl-modifying reagent. Purified AGPAT6 protein possessed GPAT activity but not AGPAT activity. Using [¹³C₇]oleic acid labeling and mass spectrometry, we found that overexpression of AGPAT6 increased both lysophosphatidic acid and phosphatidic acid levels in cells. In these studies, total triglyceride and phosphatidylcholine levels were not significantly altered, although there were significant changes in the abundance of specific phosphatidylcholine species. Human AGPAT6 is localized to endoplasmic reticulum and is broadly distributed in tissues. Membranes of mammary epithelial cells from Agpat6-deficient mice exhibited markedly reduced GPAT activity compared with membranes from wild-type mice. Reducing AGPAT6 expression in HEK293 cells through small interfering RNA knockdown suggested that AGPAT6 significantly contributed to HEK293 cellular GPAT activity. Our data indicate that AGPAT6 is a microsomal GPAT, and we propose renaming this enzyme GPAT4.

Received for publication, October 1, 2007 , and in revised form, January 9, 2008.

^* This work was supported by BayGenomics, a Program for Genomics Applications from NHLBI, National Institutes of Health, Grant UO1 HL66621. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 317-433-3535; Fax: 317-276-1417; E-mail: Guoqing_cao{at}lilly.com.

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