A Novel Mouse Model of Accelerated Non‐Alcoholic Steatohepatitis

Abstract

Non-Alcoholic Steatohepatitis (NASH) is characterized by steatosis with varying degrees of inflammation and fibrosis in the liver. The pathophysiology of NASH is not fully understood due to the lack of appropriate animal models mimicking the disease in humans. Recent studies showed that high cholesterol high fat (HCHF) diet induced NASH in mice but only after prolonged 30 weeks of feeding. We have recently shown that in transgenic mice [ISR2, with intestine-specific overexpression of active Sterol Response Binding Element Protein 2 (SREBP2)], intestinal cholesterol synthesis was significantly increased resulting in hypercholesterolemia. Since high cholesterol has been indicated to be a risk factor for NASH, we hypothesized that ISR2 mice will develop a more severe diet-induced NASH. Our data showed that HCHF feeding to ISR2 mice resulted in accelerated (15 wks versus 30 wks) and more severe NASH compared to wild type animals. HCHF feeding (15 wks) to ISR2 mice led to a significant increase in the hepatic ...