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Papers In Press, published online ahead of print July 1, 2010
J. Lipid Res., doi:10.1194/jlr.M006304

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Journal of Lipid Research, Vol. 51, 1971-1981, July 2010
Copyright © 2010 by American Society for Biochemistry and Molecular Biology

Research Articles

GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis^[S]

Dandan Shan^*, Jian-liang Li, Leeying Wu, Dongmei Li^*, Jonathan Hurov^*, James F. Tobin^*, Ruth E. Gimeno^1,* and Jingsong Cao^1,*

^* Biocorrection Research Unit, Pfizer, Cambridge, MA 02140
Bioinformatics Core Sciences, Pfizer, Cambridge, MA 02140

¹ To whom correspondence should be addressed. email: Jingsong.cao{at}pfizer.com (J.C.); ruth.gimeno{at}pfizer.com (R.E.G).

Acyl-CoA:glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step during de novo synthesis of glycerolipids. Mammals have at least four GPAT isoforms. Here we report the further characterization of the two recently identified microsomal GPAT3 and GPAT4. Both enzymes are highly expressed in adipose tissues. However, while GPAT3 is highly (60-fold) induced during adipocyte differentiation, GPAT4 induction is only modest (5-fold), leading to a lower abundance of GPAT4 mRNA in adipocytes. While overexpression of GPAT3 and GPAT4 in either insect or mammalian cells results in a comparable increase of GPAT activity, shRNA-mediated knockdown of GPAT3, but not GPAT4, in 3T3-L1 adipocytes led to a significant decrease in GPAT activity, a profound inhibition of lipid accumulation, and a lack of expression of several adipogenic markers during adipocyte differentiation. These data suggest that GPAT3 may encode the major GPAT isoform in adipocytes and play an important role in adipogenesis. Furthermore, we have shown that both GPAT3 and GPAT4 are phosphorylated by insulin at Ser and Thr residues, leading to increased GPAT activity that is sensitive to wortmannin. Our results reveal a link between the lipogenic effects of insulin and microsomal GPAT3 and GPAT4, implying their importance in glycerolipid biosynthesis.

Supplementary key words AGPAT6 • acyltransferase • triacylglycerol • phospholipid

Abbreviations: AGPAT, acyl-CoA:acylglycerol-3-phosphate acyltransferase; BAT, brown adipose tissue; C/EBP, CCAAT/enhancer binding protein alpha; DAG, diacylglycerol; DGAT, acyl-CoA:diacylglycerol acyltransferase; ER, endoplasmic reticulum; G3P, glycerol-3-phosphate; GPAT, acyl-CoA:glycerol-3-phosphate acyltransferase; LPAAT, lysophosphatidic acid acyltansferase; NEM, N-ethylmaleimide; PPAR, peroxisome proliferators-activated receptor gamma; Q-PCR, quantitative PCR; SREBP1c, sterol regulatory element binding protein 1c; TAG, triacylglycerol; WAT, white adipose tissue

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