Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. Steatosis is the initial, most frequent hepatic manifestation that occurs in response to acute as well as chronic ethanol consumption. Although steatosis is reversible, it is now established that the severity of steatosis predicts the progression of liver disease to more advanced stages including fibrosis and cirrhosis. Alcohol causes hepatic steatosis by enhancing de novo lipogenesis and impairing fatty acid beta-oxidation system with subsequent susceptibility to injury by inflammatory cytokines, particularly TNF. However, gaps remain in our understanding of alcohol-responsive mechanisms that contribute to dysregulation of genes involved in hepatic steatosis and subsequent cytokine hepatotoxicity. Cyclic AMP (cAMP), through activation of protein kinase A (PKA), has been shown to modulate genes involved in lipid metabolism and apoptosis.!cAMP levels are tightly regulated through biosynthesis by adenyl cylases (ACs) and hydrolysis by phosphodiesterases (PDEs). Our earlier work shows that expression of cAMP-specific PDE4 is significantly increased in response to alcohol exposure in monocytes/macrophages including hepatic Kupffer cells. Notably, our recent preliminary data suggest that ethanol exposure of primary mouse hepatocytes leads to a significant up-regulation of the PDE4 sub-family of enzymes, PDEA, B and D. Based on these findings we postulate that chronic ethanol feeding decreases cAMP levels in hepatocytes in a PDE4-dependent manner. There is no FDA-approved therapy for any stage of alcoholic liver disease (ALD). The most widely-used (off-label) drug therapies are glucocorticoids and pentoxifylline (PTX). Unfortunately, an important subset of AH patients treated with glucocorticoids have "steroid resistance", and some patients have contraindications to steroid therapy. PTX is a broad spectrum PDE inhibitor with only a weak PDE4 inhibitor activity, and the data available from the limited studies suggest a positive intervention effect. Hence, a more directed intervention aimed at inhibiting PDE4 may be significantly more effective. In this regard our recent preliminary data show that treatment with PDE4 specific inhibitor, rolipram, markedly inhibits hepatic steatosis in ethanol-fed animals. Our central hypothesis is that alcohol exposure increases cAMP degrading PDE4 expression in hepatocytes lowering cAMP levels with a resultant increase in lipogenesis and a decrease in fatty acid beta oxidation, leading to the development of steatosis and sensitization to TNF-induced toxicity. Importantly, as a corollary, lowering PDE4 activity may provide a significant therapeutic approach. The specific objectives of these mechanistic as well as translational studies are 1) to examine the effect of alcohol exposure on hepatocyte PDE4 expression, cAMP metabolism and development of hepatic steatosis and injury and 2) to determine the role of PDE4 subclasses and effect of PDE4 inhibition on the development of alcohol induced hepatic steatosis and injury. Our future goal is to provide a conceptual basis for targeting PDE4 activity as a clinical treatment for alcoholic patients. !

Public Health Relevance

This project will determine the contributing role of dysregulated hepatocyte PDE4/cAMP homeostasis in the development of alcohol-induced hepatic steatosis and injury and examine the efficacy of PDE4 inhibition in the prevention and treatment of alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA022189-01A1
Application #
8638593
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2014-02-05
Project End
2016-01-31
Budget Start
2014-02-05
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$215,625
Indirect Cost
$71,875
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292