Hepatocyte retinoid X receptor α-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury

Maxwell Afari Gyamfi, Lin He, Samuel William French, Ivan Damjanov, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Hepatocyte retinoid X receptor α (RXRα)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXRα-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 RXRα-deficient mice. Wild-type and hepatocyte RXRα-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 RXRα-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 RXRα deficiency. Ethanol induced L-FABP mRNA and protein in wildtype 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)-κB binding activity in hepatocyte RXRα-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 wildtype 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 RXRα-deficient mice. Taken together, after ethanol treatment, hepatocyte RXRα deficiency results in lack of L-FABP induction, increased hepatic free fatty acids, NF-κB activation, and proinflammatory cytokines production and a lack of STAT3 activation, which in part may contribute to alcohol-induced liver damage.

Original languageEnglish (US)
Pages (from-to)443-453
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

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Retinoid X Receptors
Hepatocytes
Homeostasis
Alcohols
Cytokines
Lipids
Ethanol
Liver
Wounds and Injuries
Fatty Acid-Binding Proteins
Nonesterified Fatty Acids
Messenger RNA
Transcription Factor 3
Diet
STAT3 Transcription Factor
Lipid Metabolism
Chemokines

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hepatocyte retinoid X receptor α-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury. / Gyamfi, Maxwell Afari; He, Lin; French, Samuel William; Damjanov, Ivan; Wan, Yu-Jui Yvonne.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 2, 02.2008, p. 443-453.

Research output: Contribution to journalArticle

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