This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 28/10/1738    most recent ATVBAHA.108.171538v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Z. Articles by Finck, B. N. Search for Related Content PubMed PubMed Citation Articles by Chen, Z. Articles by Finck, B. N. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1738.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Alterations in Hepatic Metabolism in fld Mice Reveal a Role for Lipin 1 in Regulating VLDL-Triacylglyceride Secretion

Zhouji Chen; Matthew C. Gropler; Jin Norris; John C. Lawrence, Jr; Thurl E. Harris; Brian N. Finck

From the Department of Medicine (Z.C., M.C.G., J.N., B.N.F.), Washington University School of Medicine, St. Louis, Mo; and the Department of Pharmacology (J.C.L., T.E.H.), University of Virginia School of Medicine, Charlottesville.

Correspondence to Brian N. Finck, Center for Human Nutrition, Washington University School of Medicine, 660 S Euclid Ave, Box 8031, St. Louis, MO 63110. E-mail bfinck{at}im.wustl.edu

Objective— Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and in the cytosol as an enzyme catalyzing the penultimate step in phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate the effects of lipin 1 on hepatic TAG synthesis and secretion by gain-of-function and loss-of-function approaches.

Methods and Results— Rates of TAG synthesis were not impaired in hepatocytes isolated from adult lipin 1–deficient (fld) mice and were actually increased in 14-day-old fld mice. Additionally, compared to littermate controls, VLDL-TAG secretion rates were markedly increased in fld mice of both ages. Lipin 1 overexpression did not alter TAG synthesis rates but significantly suppressed VLDL-TAG secretion. The lipin 1-mediated suppression of VLDL-TAG secretion was linked to the peptide motif mediating its transcriptional-regulatory effects. However, the expression of candidate genes required for VLDL assembly and secretion was unaltered by lipin 1 activation or deficiency. Finally, the hepatic expression of lipin 1 was diminished in obese insulin-resistant mice, whereas adenoviral-mediated overexpression of lipin 1 in liver of these mice inhibits VLDL-TAG secretion and improves hepatic insulin signaling.

Conclusions— Collectively, these studies reveal new and unexpected effects of lipin 1 on hepatic TAG metabolism and obesity-related hepatic insulin resistance.

Key Words: lipin 1 • liver • triglyceride • VLDL secretion • dyslipidemia

This article has been cited by other articles:

				J. Donkor, P. Zhang, S. Wong, L. O'Loughlin, J. Dewald, B. P.C. Kok, D. N. Brindley, and K. Reue A Conserved Serine Residue Is Required for the Phosphatidate Phosphatase Activity but Not the Transcriptional Coactivator Functions of Lipin-1 and Lipin-2 J. Biol. Chem., October 23, 2009; 284(43): 29968 - 29978. [Abstract] [Full Text] [PDF]

				K. Reue and J. R. Dwyer Lipin proteins and metabolic homeostasis J. Lipid Res., April 1, 2009; 50(Supplement): S109 - S114. [Abstract] [Full Text] [PDF]

				M. C. Gropler, T. E. Harris, A. M. Hall, N. E. Wolins, R. W. Gross, X. Han, Z. Chen, and B. N. Finck Lipin 2 Is a Liver-enriched Phosphatidate Phosphohydrolase Enzyme That Is Dynamically Regulated by Fasting and Obesity in Mice J. Biol. Chem., March 13, 2009; 284(11): 6763 - 6772. [Abstract] [Full Text] [PDF]

				K. Reue and D. N. Brindley Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism J. Lipid Res., December 1, 2008; 49(12): 2493 - 2503. [Abstract] [Full Text] [PDF]