2298-PUB: Estradiol Protects Female ApoE KO Mice against Nonalcoholic Steatohepatitis

Lifestyle and increased consumption of high fat diets contribute greatly to the development of obesity, insulin resistance, type 2 diabetes (DM2), and cardiovascular diseases, which are less prevalent in young women than in men of the same age or postmenopausal women. One of the consequences of the Western lifestyle and high fat diet is Nonalcoholic Fatty Liver Disease (NAFLD) and its aggressive form, Nonalcoholic Steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular cancer (HCC) and is rapidly becoming the leading cause for end-stage liver disease or liver transplantation. Therefore, we evaluated if female mice were protected against Western Diet (WD)-induced NASH in apolipoprotein E (ApoE) KO animals. Female ApoE KO mice ovariectomized (OVX) or sham operated (SHAM) were fed a WD for 7 weeks. Whole-body fat was increased by ∼65% (P<0.001) in OVX mice associated with an increase of glucose intolerance of by ∼75% (P<0.01) and increased hepatic triglycerides (TAG) by 130% (P<0.01) compared with SHAM mice. OVX mice also displayed increased plasma ALT (∼130, P<0.001) and AST (∼65%, P<0.05) compared with SHAM mice. These data were associated with increased hepatic inflammation in OVX mice, demonstrated by an increased of F4/80 of by ∼70% (P<0.01). Hepatic fibrosis was also increased in OVX mice by ∼80% (P<0.001) compared with SHAM mice. Estradiol treatment of OVX mice reversed some of these effects, reducing whole-body fat (P<0.01), glucose intolerance (P<0.01), and hepatic TAG content (P<0.001). Taken together, these data support the hypothesis that estradiol protects OVX mice from WD-induced NASH and glucose intolerance, by protecting female mice against hepatic steatosis, inflammation and fibrosis.