Research Article
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* | |
| Liver Research Center, Divisions of Gastroenterology and Neuropathology, and Departments of Medicine, Pathology, Neurology, and Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, USA | |
| *Corresponding Author : | Suzanne M. de la Monte, MD, MPH Pierre Galletti Research Building Rhode Island Hospital, 55 Claverick Street Room 419, Providence,USA Tel: 401-444-7364 Fax: 401-444-2939 E-mail: Suzanne_DeLaMonte_MD@Brown.edu |
| Received October 31, 2014; Accepted November 10, 2014, Published November 17, 2014 | |
| Citation: Borgas DL, Deochand C, Tong M, de la Monte SM (2014) PPAR Agonist Effects on Notch Signaling Mediators in Experimental Chronic Alcohol-Induced Steatohepatitis. Biochem Physiol 3:145. doi:10.4172/2168-9652.1000145 | |
| Copyright: © 2014 Borgas DL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
Abstract
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.
