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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Hepatocyte Retinoid X Receptor -Dependent Regulation of Lipid Homeostasis and Inflammatory Cytokine Expression Contributes to Alcohol-Induced Liver Injury

Departments of Pharmacology, Toxicology, and Therapeutics (M.A.G., L.H., Y.-J.Y.W.) and Pathology and Laboratory Medicine (I.D.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pathology, Harbor-University of California Los Angeles Medical Center, Torrance, California (S.W.F.)

Hepatocyte retinoid X receptor (RXR)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXR-mediated pathways are implicated in lipid homeostasis and the inflammatory response, we hypothesized that a compromise in lipid metabolism and associated production of proinflammatory mediators are responsible for the hepatotoxicity observed in ethanol-treated hepatocyte RXR-deficient mice. Wild-type and hepatocyte RXR-deficient mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks. After ethanol treatment, serum ALT levels increased significantly (4-fold) in hepatocyte RXR-deficient mice, but not in the wild-type mice. Hepatic liver fatty acid binding protein (L-FABP) mRNA and protein levels were reduced due to RXR deficiency. Ethanol induced L-FABP mRNA and protein in wild-type mice and provided protection against nonesterified fatty acid toxicity; however, this effect was absent in the mutant mice. Accordingly, hepatic nonesterified fatty acid level was increased in ethanol-fed mutant mice. Ethanol increased nuclear factor (NF)-B binding activity in hepatocyte RXR-deficient mice, but not in wild-type mice. In agreement, hepatic mRNA levels of proinflammatory cytokines and chemokines were increased to a greater extent in the mutant than in wild-type mice. Furthermore, signal transducer and activator of transcription factor (STAT) 3 and associated Bcl-xL induction was observed in ethanol-fed wild-type mice but not in ethanol-fed hepatocyte RXR-deficient mice. Taken together, after ethanol treatment, hepatocyte RXR deficiency results in lack of L-FABP induction, increased hepatic free fatty acids, NF-B activation, and proinflammatory cytokines production and a lack of STAT3 activation, which in part may contribute to alcohol-induced liver damage.

Address correspondence to: Dr. Yu-Jui Yvonne Wan, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417. E-mail: ywan{at}kumc.edu

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