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J. Biol. Chem., Vol. 282, Issue 6, 3450-3457, February 9, 2007

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Three Mammalian Lipins Act as Phosphatidate Phosphatases with Distinct Tissue Expression Patterns^*

Jimmy Donkor, Meltem Sariahmetoglu, Jay Dewald, David N. Brindley¹, and Karen Reue²

From the Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095 and Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

We previously identified mutations in the Lpin1 gene, encoding lipin-1, as the underlying cause of lipodystrophy in the fatty liver dystrophy (fld) mutant mouse. Lipin-1 is normally expressed at high levels in adipose tissue and skeletal muscle, and deficiency in the fld mouse causes impaired adipose tissue development, insulin resistance, and altered energy expenditure. We also identified two additional lipin protein family members of unknown function, lipin-2 and lipin-3. Han et al. (Han, G. S., Wu, W. I., and Carman, G. M. (2006) J. Biol. Chem. 281, 9210–9218) recently demonstrated that the single lipin homolog in yeast, Smp2, exhibits phosphatidate phosphatase type-1 (PAP1) activity, which has a key role in glycerolipid synthesis. Here we demonstrate that lipin-1 accounts for all of the PAP1 activity in white and brown adipose tissue and skeletal muscle. However, livers of lipin-1-deficient mice exhibited normal PAP1 activity, indicating that other members of the lipin protein family could have PAP1 activity. Consistent with this possibility, recombinant lipin-2 and lipin-3 possess PAP1 activity. Each of the three lipin family members showed Mg²⁺-dependent activity that was specific for phosphatidate under the conditions employed. The different lipins showed distinct tissue expression patterns. Our results establish the three mammalian lipin proteins as PAP1 enzymes and explain the biochemical basis for lipodystrophy in the lipin-1-deficient fld mouse.

Received for publication, November 20, 2006

^* This work was supported in part by National Institutes of Health Grant HL-28481 (to K. R.), Genomic Analysis Training Grant S-T32-HG002536 (to J. D.), and by the Canadian Institute of Health Research Grant MOP 49491 (to D. N. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Recipient of a Medical Scientist Award from the Alberta Heritage Foundation for Medical Research. To whom correspondence may be addressed: Signal Transduction Research Group, Dept. of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-2078; Fax: 780-492-3383; E-mail: david.brindley{at}ualberta.ca. ²To whom correspondence may be addressed: Dept. of Human Genetics, David Geffen School of Medicine at University of California Los Angeles (UCLA), Gonda 6506A, 695 Charles E. Young Dr. South, Los Angeles, CA 90095. Tel.: 310-794-5631; Fax: 310-794-5446; E-mail: reuek{at}ucla.edu.

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