Critical role of phosphodiesterase 4 in alcohol induced hepatic steatosis (653.11)

Abstract

Alcohol induced hepatic steatosis is a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) has been shown to play a significant role in the regulation of hepatic lipogenesis. Our recent work demonstrated that cAMP degrading PDE4 enzymes are expressed in the liver. The aim of this study was to examine the effect of alcohol on hepatic PDE4 expression and its potential role in the development of alcoholic steatosis. C57Bl/6 and pde4b knockout (pde4b‐/‐) mice were pair‐fed control or ethanol liquid diets for 4 weeks. One group of mice received rolipram, a PDE4 specific inhibitor. We demonstrated that alcohol feeding leads to an early up‐regulation of PDE4B and D accompanied by increased expression of fatty acid synthase and SREBP‐1. Pde4b‐/‐ mice and mice treated with rolipram were significantly protected from alcohol induced hepatic steatosis. An increase in CYP2E1 expression was similar in wild type and pde4b‐/‐ mice, but was decreased by rolipram. These results indicate that hepatic PDE4B plays a significant role in regulating lipogenesis, whereas PDE4D affects CYP2E1 expression and alcohol metabolism. Taken together, these data suggest that hepatic PDE4 expression is a clinically relevant target, and its inhibition can significantly attenuate the development of alcohol induced hepatic steatosis.Grant Funding Source: Supported by NIH, DOD and Veterans Administration