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Journal of Lipid Research, Vol. 50, 439-445, March 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress

Jodi M. Maglich, David C. Lobe and John T. Moore¹

Metabolic Pathways, GlaxoSmithKline, Research Triangle Park, Durham, NC

Published, JLR Papers in Press, October 21, 2008.

¹ To whom correspondence should be addressed. e-mail: John.T.Moore{at}gsk.com

The nuclear receptor constitutive androstane receptor (CAR) (NR1I3) regulates hepatic genes involved in xenobiotic detoxification as well as genes involved in energy homeostasis. We provide data that extend the role of CAR to regulation of serum triglyceride levels under conditions of metabolic/nutritional stress. The typically high serum triglyceride levels of ob/ob mice were completely normalized when crossed onto a Car^–/– (mice deficient for the Car gene) genetic background. Moreover, increases in serum triglycerides observed after a high-fat diet (HFD) regime were not observed in Car^–/– animals. Conversely, pharmacological induction of CAR activity using the selective mouse CAR agonist TCPOBOP during HFD feeding resulted in a CAR-dependent increase in serum triglyceride levels. A major regulator of hepatic fatty oxidation is the nuclear receptor PPAR (NR1C1). The expression of peroxisome proliferator-activated receptor alpha (PPAR) target genes was inversely related to the activity of CAR. Consistent with these observations, Car^–/– animals exhibited increased hepatic fatty acid oxidation. Treatment of mice with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) significantly decreased expression of PPAR mRNA as well as Cyp4a14, CPT1, and cytosolic Acyl-CoA thioesterase (CTE) in the liver. These data have implications in disease therapy such as for diabetes and nonalcoholic steatohepatitis (NASH).

Supplementary key words serum triglycerides • peroxisome proliferator-activated receptor alpha • non-alcoholic fatty liver disease • nonalcoholic steatohepatitis

Abbreviations: CAR, constitutive androstane receptor; Car^–/– mice, mice deficient for the Car gene; CTE, cytosolic Acyl-CoA thioesterase; HFD, high-fat diet; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor alpha; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; WT, wild-type

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