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Journal of Lipid Research, Vol. 50, 47-58, January 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL

Maroun Bou Khalil^*, Meenakshi Sundaram^*, Hong-Yu Zhang^*, Philip H. Links^*, Jennifer F. Raven^*, Boripont Manmontri, Meltem Sariahmetoglu, Khai Tran^*, Karen Reue, David N. Brindley and Zemin Yao^1,*

^* Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two tables.

Published, JLR Papers in Press, September 3, 2008.

This work was supported by Canadian Institutes of Health Research (CIHR) Grant MT-15486 to Z.Y., and grant MOP 81137 to D.N.B. Z.Y. is a Career Investigator of the Heart and Stroke Foundation of Ontario, and D.N.B. is a recipient of a Medical Scientist Award from the Alberta Heritage Foundation for Medical Research.

¹ To whom correspondence should be addressed. e-mail: zyao{at}uottawa.ca

Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG). PAP-1 activity is encoded by members of the lipin family, including lipin-1 (1 and 1β), -2, and -3. We determined the effect of lipin-1 expression on the assembly and secretion of very low density lipoproteins (VLDL) using McA-RH7777 cells. Expression of lipin-1 or -1β increased the synthesis and secretion of [³H]glycerol-labeled lipids under either basal- or oleate-supplemented conditions. In the presence of oleate, the increased TAG secretion was mainly associated with VLDL₁ (S_f > 100) and VLDL₂ (S_f 20–100). Expression of lipin-1 or -1β increased secretion efficiency and decreased intracellular degradation of [³⁵S]apolipoprotein B-100 (apoB100). Knockdown of lipin-1 using specific short interfering RNA decreased secretion of [³H]glycerolipids and [³⁵S]apoB100 even though total PAP-1 activity was not decreased, owing to the presence of lipin-2 and -3 in the cells. Deletion of the nuclear localization signal sequences within lipin-1 not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1 mutant failed to promote [³⁵S]apoB100 synthesis or secretion, and showed compromised stimulation in [³H]TAG synthesis and secretion. Thus, alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion.

Supplementary key words fatty liver dystrophy • hepatosteatosis • triacylglycerol • hypertriglyceridemia • diabetes • dexamethasone • insulin

Abbreviations: apo, apolipoprotein; DAG, diacylglycerol; ER, endoplasmic reticulum; MTP, microsomal triglyceride transfer protein; NLS, nuclear localization signal; PA, phosphatidate; PAP, phosphatidate phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PGC-1, PPAR coactivator protein-1; PPAR, peroxisome proliferator-activated receptor-; siRNA, short interfering RNA; TAG, triacylglycerol

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