The goal of this project is to study the mechanism underlying nuclear receptor retinoid x receptor et (RXR-alpha)-mediated pathways on regulating S-adenosyl-L-methionine (SAMe) homeostasis. The main hypothesis is that RXR-alpha-mediated pathways either directly or indirectly control SAMe synthesis and alter the levels of glutathione and phosphatidylcholine in the liver, which consequently play a crucial role in the development of alcoholic liver disease (ALD). Most of the retinol and alcohol studies rely on either feeding animals with excess amount of retinoids or introducing animals with retinol deficient diet. Feeding animals with retinoids can be toxic. Retinol deficiency can also cause many unwanted effects. Knockout technology avoids these potential problems. Tissue specific knockout further allows studying the function of the gene in a cell type specific manner without affecting the gene function systemically. We have established an animal model in that the RXR-alpha gene is knocked out only in the hepatocyte. RXR-alpha is highly expressed in the liver and is required for almost all the nuclear receptor-mediated pathways. Therefore, hepatocyte RXR-alpha deficient mouse serves as an excellent model for studying retinoid signaling in alcoholic liver disease. When hepatocyte RXR-alpha is deficient, liver retinoic acid is elevated, alcohol elimination rate is increased and alcohol-induced liver damage becomes more severe. In addition, the expression of more than ten genes encoding enzymes involved in the SAMe pathway is altered. Those data indicate that RXR-alpha, SAMe and ALD are intricately interlinked.
Two specific aims are proposed to study the direct and indirect effect of RXR-alpha on SAMe homeostasis. First is to examine how RXR-alpha-mediated pathways regulate alcohol metabolism, which may indirectly control SAMe synthesis and affect the development of ALD. Second is to characterize how RXR-alpha-mediated pathways regulate genes encoding enzymes in the SAMe pathway and directly control SAMe homeostasis. RXR-alpha-mediated pathways including PPARcz and 3' and RXR-alpha homodimer and others will be studied. The effect of those nuclear receptor ligands on regulating SAMe synthesis will be analyzed. The proposed study not only allows us to understand how nuclear receptors regulate SAMe homeostasis, it also provides an opportunity to identify potential therapeutical targets and treatment agents for ALD.
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