TY - JOUR
T1 - Hepatocyte retinoid X receptor α-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury
AU - Gyamfi, Maxwell Afari
AU - He, Lin
AU - French, Samuel William
AU - Damjanov, Ivan
AU - Wan, Yu-Jui Yvonne
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38749127945&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38749127945&partnerID=8YFLogxK
U2 - 10.1124/jpet.107.132258
DO - 10.1124/jpet.107.132258
M3 - Article
C2 - 17975011
AN - SCOPUS:38749127945
VL - 324
SP - 443
EP - 453
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 2
ER -