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Journal of Lipid Research, Vol. 49, 1056-1067, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically^*

Boripont Manmontri^1,*, Meltem Sariahmetoglu^1,*, Jimmy Donkor, Maroun Bou Khalil, Meenakshi Sundaram, Zemin Yao, Karen Reue, Richard Lehner^** and David N. Brindley^2,*

^* Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
^** Canadian Institute of Health Research Group on the Molecular and Cell Biology of Lipids, Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2S2, Canada
Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada
Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

^* This work was supported by awards from the Canadian Institute of Health Research (Grant MOP 81137), the Diabetes Association (Brooks and District), and the Alberta Heart and Stroke Foundation to D.N.B., by Canadian Institute of Health Research Grant MT-15486 to Z.Y., and by U. S. National Institutes of Health Grant HL-28481 to K.R. D.N.B. is the recipient of a Medical Scientist Award from the Alberta Heritage Foundation for Medical Research.

Published, JLR Papers in Press, February 15, 2008.

¹ B. Manmontri and M. Sariahmetoglu contributed equally to this work.

² To whom correspondence should be addressed. e-mail: david.brindley{at}ualberta.ca

Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for β-oxidation or VLDL secretion. PAP1 catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAP1 enzymes in liver include lipin-1A and -1B (alternatively spliced isoforms) and two distinct gene products, lipin-2 and lipin-3. We determined the mechanisms by which the composite PAP1 activity is regulated using rat and mouse hepatocytes. Levels of lipin-1A and -1B mRNA were increased by dexamethasone (dex; a synthetic GC), and this resulted in increased lipin-1 synthesis, protein levels, and PAP1 activity. The stimulatory effect of dex on lipin-1 expression was enhanced by glucagon or cAMP and antagonized by insulin. Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAP1 activity is attributable specifically to enhanced lipin-1 expression. This work provides the first evidence for the differential regulation of lipin activities. Selective lipin-1 expression explains the GC and cAMP effects on increased hepatic PAP1 activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.

Supplementary key words β-oxidation • diabetes • ethanol ingestion • fasting • glucagon • hypertriglyceridemia • steatosis • triacylglycerol synthesis

Abbreviations: CPTcAMP, 8-(4-chlorophenylthio) cyclic AMP; DAG, diacylglycerol; dex, dexamethasone; ER, endoplasmic reticulum; GC, glucocorticoid; LPP, lipid phosphate phosphatase; PA, phosphatidate; PAP1, phosphatidate phosphatase; PGC-1, peroxisome proliferator-activated receptor-coactivator-1; TAG, triacylglycerol

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