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

Abstract

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 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)-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 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 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.In the adult liver, the nuclear receptor, retinoid X receptor ␣ (RXR␣), is the most abundant among the three RXR isoforms (␣, ␤, and ␥) (Mangelsdorf et al., 1992).

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

“…In contrast, PPAR-␣ deficiency could lead to elevated TNF-␣ expression levels and then result in hepatocyte steatosis, apoptosis, and inflammatory cell infiltration (49)(50)(51). Meanwhile TNF-␣ can provoke more severe oxidative stress, hepatitis, and apoptosis via downregulating hepatic PPAR-␣ expression (52). Therefore, in PZA-treated rats, L-FABP-mediated PPAR-␣ downregulation appears to be a response to hepatotoxicity resulting from zebrafish larva liver cell inflammation and apoptosis.…”

Oncogenic Potential of Retinoic Acid Receptor-γ in Hepatocellular Carcinoma

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Role of Pregnane X Receptor in Obesity and Glucose Homeostasis in Male Mice

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