on July 31, 2008
Published online before print July 31, 2008, doi: 10.1161/ATVBAHA.108.171538
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Submitted on February 29, 2008
Accepted on July 21, 2008
Alterations in Hepatic Metabolism in fld Mice Reveal a Role for Lipin 1 in Regulating VLDL-Triacylglyceride Secretion
Zhouji Chen ;
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.
* To whom correspondence should be addressed. 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
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