SAT-152 Loss of Hepatocyte PPARγ Expression Ameliorates Steatosis in Mice Fed a High-Fat, Cholesterol, and Fructose Diet, but Not in Mice Fed a Methionine- and Choline-Deficient Diet

Hepatic PPARγ expression is positively associated with the progression of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) in mice and humans. Although PPARγ agonists, thiazolidinediones (TZD), could be used to treat patients with NASH, these drugs reduced steatosis only in some patients with NASH, while it exacerbated steatosis in obese mice. Several mouse models with congenital knockout or overexpression of hepatic PPARγ have been used to study the actions and relevance of hepatocyte PPARγ in the development of steatosis. However, the mechanisms that hepatocyte PPARγ regulates to promote steatosis are not fully understood. Our group has previously reported that adult-onset hepatocyte-specific PPARγ knockout (aHepPPARγKO) mice fed a high fat diet (60% Kcal from fat) developed adiposity similar to PPARγ-intact controls, but aHepPPARγKO mice showed a dramatic reduction in steatosis, associated with reduced hepatic Cd36-mediated fatty acid uptake. Here, we fed aHepPPARγKO mice two different diets that produce steatosis and NASH to determine if loss of hepatocyte PPARγ expression reduced hepatic lipid levels associated with a reduction in Cd36 expression. Specifically, aHepPPARγKO and control mice were generated by injecting 10 wk-old male PPARγ-floxed littermate mice with a single dose of adeno-associated virus serotype 8 (AAV8) expressing hepatocyte-specific Cre recombinase or a AAV8-null vector, respectively. Two weeks later, aHepPPARγKO and control mice were fed either a methionine- and choline-deficient diet (MCD) for 3 weeks or a high-fat, cholesterol and fructose diet (HFCFD) diet for 8 weeks. The expression of hepatic PPARγ and Cd36 was significantly increased in MCD- and HFCF-fed control mice as compared to their respective control diet-fed controls. Of note, aHepPPARγKO reduced the expression of hepatic PPARγ (by >85%) and Cd36 (by >35-65%). Overall, MCD-fed mice showed reduced body weight, fat mass, and plasma cholesterol levels, while HFCFD-fed mice showed increased body weight and gonadal fat mass, and reduced plasma NEFA levels as compared to their respective control diet-fed littermates. Independent of diet, aHepPPARγKO did not alter body weight, adiposity, or the levels of plasma lipids. However, aHepPPARγKO reduced steatosis in HFCFD-fed mice, but not in MCD-fed mice. Interestingly, the levels of hepatic oleic [18:1(n-9)] and linoleic [18:2(n-6)] acids were, in fact, increased in MCD-fed aHepPPARγKO mice, while the levels of hepatic palmitoleic [16:1(n-7)] and oleic [18:1(n-9)] acids were reduced in HFCFD-fed aHepPPARγKO mice. Taken together, these data suggest that hepatocyte PPARγ serves as a steatogenic factor only in HFCFD-fed mice and not in MCD-fed mice, and this may be due to diet-dependent effects: nature of the development of steatosis and/or changes in adipose tissue.