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PPAR Agonist Effects on Notch Signaling Mediators in Experimental Chronic Alcohol-Induced Steatohepatitis

Diana L Borgas, Chetram Deochand, Ming Tong, and Suzanne M de la Monte

Background: Aspartyl-Asparaginyl-Β-Hydroxylase (ASPH) is a downstream target of insulin and IGF signaling and promotes cell motility for liver remodeling and repair. ASPH functions in part by activating Notch and HIF-1α. PPAR agonists can ameliorate steatohepatitis, hepatic insulin resistance, and reduced ASPH expression in experimental alcoholic liver disease. Herein, we examine the effects of PPAR-α, PPAR-δ, and PPAR-γ agonists on Notch and HIF-1α signaling. Methods: Long Evans rats were chronically fed control or ethanol-containing diets and treated with vehicle, or a PPAR-α, PPAR-δ, or PPAR-γ agonist. ASPH, Notch, and HIF-1α-related genes and proteins were measured in liver. Results: ASPH, Notch, and HIF-1α signaling genes and/or proteins were inhibited by chronic ethanol feeding. PPAR-δ and/or PPAR-γ agonists normalized ASPH, HIF-1α, and PCNA protein in ethanol-exposed livers. In contrast, Notch signaling through HES-1 was not restored. Conclusion: Therapeutic effects of PPAR-δ and PPAR-γ agonists in alcoholic liver disease are mediated by post-translational mechanisms that bolster ASPH-HIF-1α signaling. Alternative strategies are needed to circumvent ethanol-mediated uncoupling of cross-talk among insulin/IGF-1/ASPH-Notch networks.