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Journal of Lipid Research, Vol. 49, 2493-2503, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism^*

Karen Reue^1,* and David N. Brindley

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

^* The authors gratefully acknowledge support from the National Heart, Lung, and Blood Institute (HL-28481 and HL-90553 to K.R.) and the Heart and Stroke Foundation of Alberta, NWT & Nunavut (to D.N.B.).

Published, JLR Papers in Press, September 12, 2008.

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

Phosphatidate phosphatase-1 (PAP1) enzymes have a key role in glycerolipid synthesis through the conversion of phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine. PAP1 activity in mammals is determined by the lipin family of proteins, lipin-1, lipin-2, and lipin-3, which each have distinct tissue expression patterns and appear to have unique physiological functions. In addition to its role in glycerolipid synthesis, lipin-1 also operates as a transcriptional coactivator, working in collaboration with known nuclear receptors and coactivators to modulate lipid metabolism gene expression. The requirement for different lipin activities in vivo is highlighted by the occurrence of lipodystrophy, insulin resistance, and neuropathy in a lipin-1-deficient mutant mouse strain. In humans, variations in lipin-1 expression levels and gene polymorphisms are associated with insulin sensitivity, metabolic rate, hypertension, and risk for the metabolic syndrome. Furthermore, critical mutations in lipin-2 result in the development of an inflammatory disorder in human patients. A key goal of future studies will be to further elucidate the specific roles and modes of regulation of each of the three lipin proteins in key metabolic processes, including triglyceride and phospholipid synthesis, fatty acid metabolism, and insulin sensitivity.

Supplementary key words triacylglycerol • lipodystrophy • obesity • insulin resistance • adipose tissue • muscle • liver • transcriptional coactivator

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