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"ALTERATIONS IN HEPATIC cAMP SIGNALING FOLLOWING CHRONIC ALCHOL CONSUMPTION"

by
Victoria L. Prince
MD/Ph.D. Program
B.Sc. 2005, Rutgers The State University



Thesis Advisor: Andrew P. Thomas, Ph.D.
Professor
Department of Pharmacology and Physiology

Thursday, January 12, 2012
2:00 P.M., H-609, Pharmacology Conference Room


Abstract

Diseases associated with alcohol abuse are major public health concerns because of a number of well-documented pathological conditions. Alcohol-induced liver disease is responsible for much of the morbidity and mortality associated with alcohol abuse, yet the exact mechanisms by which such conditions occur remain elusive. Chronic and acute consumption of alcohol can lead to alterations in signal transduction in hepatocytes, but the intricacies of these alterations remain to be elucidated. The cAMP-Protein Kinase A (PKA) signaling pathway is a lynchpin of normal cellular functioning, and significant research has explored how this pathway can be altered by alcohol. Little of this research, however, has focused on liver parenchymal cells. In this study, we investigated the cAMP-PKA signaling pathway in hepatocytes from alcohol-fed animals maintained using the Lieber-DeCarli pair-feeding alcohol model. We found that after 60 days of alcohol consumption there was no global change in basal or hormone-induced cAMP concentrations between cultured cells from control and alcohol-fed animals. Neither was there any difference in basal or hormone-induced PKA activity in these cells. Chronic alcohol consumption did lead to a decrease in expression of the PKARIƒŅ regulatory subunit. A decrease in phosphorylation of the cAMP response element-binding (CREB) protein was also observed, as was a decrease in the mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting step of long chain fatty acid metabolism, which is at least partially under transcriptional regulation by CREB. Furthermore, when cells from chow-fed animals were cultured with low levels of ethanol, a similar decrease in PKARIƒŅ expression was seen within 48 hours, and this phenomenon was reproducible with the non-metabolizable cAMP analog cpt-cAMP. This suggests that alterations in the expression of PKARIƒŅ, which in turn may lead to changes in PKA signaling such as altered CREB phosphorylation, could be due to an acute or transitory alteration in cAMP levels that is lost in cells from animals chronically-fed ethanol that are cultured overnight. These results suggest a potential mechanism in which alcohol exposure can lead to alterations in the cAMP-PKA signaling pathway by changing the composition of regulatory subunits of PKA, changing CREB phosphorylation, and altering the translation of genes that are potentially involved in the development of fatty liver disease, the first step in the progression of alcohol-induced liver disease.


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