Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests in the United States. NAFLD represents a spectrum of disease including hepatic steatosis, steatohepatitis (NASH) and steatohepatitis with fibrosis or cirrhosis. Although NASH has been associated with obesity, diabetes, hyperlipidemia and insulin-resistance, in fact, little is known about the pathophysiology of NASH, and the molecular and cellular mechanisms responsible for the development of NASH remain virtually unexplored. The administration of a methionine- and - choline deficient (MCD) diet to mice serves as an animal model of NASH. In this proposal, we will employ the MCD model and wild-type and mutant mice to: 1) investigate the role of hepatic Phospatidylethenolamine-N-Methyltransferase (PEMT) and S-adenosylmethionine (AdoMet) in the pathophysiology of NASH; 2) to determine the import of hepatic phospatidylcholine (PC) secretion in the development of NASH; and 3) and further define the role of endotoxin in the pathophysiology of NASH. The studies will help elucidate the pathophysiology, and thus better allow for rational new therapeutic approaches, for this common hepatic disease.
