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(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

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