Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition

Abstract

Although there are small animal platforms that recapitulate some of the histological features of nonalcoholic fatty liver disease, there are no small animal models of nonalcoholic steatohepatitis (NASH) with consistent hepatocellular ballooning and progressive fibrosis that also exhibit fidelity to the human condition physiologically. We examined the metabolic and histological effects of a diet on the basis of the composition of “fast food” (high saturated fats, cholesterol, and fructose). Mice ( n = 8 in each group) were assigned to diets as follows: 1) standard chow (SC), i.e., 13% energy as fat [1% saturated fatty acids (SFA)], 2) high fat (HF), i.e., 60% energy as fat (1% SFA), and 3) fast food (FF), i.e., 40% energy as fat (12% SFA, 2% cholesterol). All three diets were supplemented with high fructose. All diets produced obesity. The HF and FF diets produced insulin resistance. Liver histology was normal in animals fed the SC diet. Steatohepatitis with pronounced ballooning and progressive fibrosis (stage 2) was observed in mice fed the FF diet. Although the HF diet produced obesity, insulin resistance, and some steatosis; inflammation was minimal, and there was no increase in fibrosis. The FF diet produced a gene expression signature of increased fibrosis, inflammation, and endoplasmic reticulum stress and lipoapoptosis. A diet based on high cholesterol, high saturated fat, and high fructose recapitulates features of the metabolic syndrome and NASH with progressive fibrosis. This represents a novel small animal model of fibrosing NASH with high fidelity to the human condition. These results highlight the contribution of dietary composition to the development of nonalcoholic fatty liver disease and NASH.

Steatosis does not impair liver regeneration after partial hepatectomy

“…Other models elicit steatosis, accompanied by manifest inflammation or severe cell damage. A novel dietary model caused characteristics similar to our model, including microvesicular steatosis but without evidence of severe inflammation after receiving a fast food diet, 34 though no data on resection or regeneration are available for this model yet. In our model, 6 weeks of WD feeding did not change cytokine release or induce severe inflammation and hepatic cell death before and after PHx.…”

Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells

“…Vehicle A prior in vivo study demonstrated the deleterious effects of increased dietary saturated fat by feeding mice a socalled "fast-food diet" that was high in saturated fat and cholesterol. These mice developed pathological symptoms of nonalcoholic steatohepatitis (NASH), in contrast to mice fed a typical high-fat diet that only developed simple steatosis without NASH symptoms ( 11 ). In vitro lipotoxicity experiments in a variety of cell lines, including Chinese hamster ovary (CHO) cells ( 10,12,13 ), pancreatic ␤ cells ( 14,15 ), breast cancer cells ( 16 ), and hepatic cells ( 6,9,(17)(18)(19), have shown that SFA overexposure is characterized by expression of proinfl ammatory cytokines, endoplasmic reticulum (ER) impairment, elevated reactive oxygen species (ROS), and eventual apoptosis without signifi cant TAG formation.…”

Hepatocytes release ceramide-enriched pro-inflammatory extracellular vesicles in an IRE1α-dependent manner

“…C56Bl/6J mice were purchased from Jackson Laboratory (Bar Harbor, ME). Twelve-week-old mice were fed either chow or a diet high in saturated fat, fructose, and cholesterol (FFC) for 24 weeks, as previously described ( 26 ). This diet recapitulates the pathologic features of human NASH.…”