Abstract
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease. Mechanisms that underlie this progression remain poorly understood, partly due to lack of good animal models that resemble human NASH. We previously showed that several metabolic syndrome features that develop in LDL receptor-deficient (LDLR-/-) mice fed a diabetogenic diet are worsened by dietary cholesterol. To test whether dietary cholesterol can alter the hepatic phenotype in the metabolic syndrome, we fed LDLR-/- mice a high-fat, high-carbohydrate diabetogenic diet (DD) without or with added cholesterol (DDC). Both groups of mice developed obesity and insulin resistance. Hyperinsulinemia, dyslipidemia, hepatic triglyceride, and alanine aminotransferase (ALT) elevations were greater with DDC. Livers of DD-fed mice showed histological changes resembling NAFLD, including steatosis and modest fibrotic changes; however, DDC-fed animals developed micro- and macrovesicular steatosis, inflammatory cell foci, and fibrosis resembling human NASH. Dietary cholesterol also exacerbated hepatic macrophage infiltration, apoptosis, and oxidative stress. Thus, LDLR-/- mice fed diabetogenic diets may be useful models for studying human NASH. Dietary cholesterol appears to confer a second "hit" that results in a distinct hepatic phenotype characterized by increased inflammation and oxidative stress.
Highlights
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease
The spectrum of changes in the liver in NAFLD ranges from simple, noninflammatory triglyceride accumulation in hepatocytes (“simple” steatosis or fatty liver) to steatosis with inflammation and fibrosis, which occasionally progresses to cirrhosis, end-stage liver disease, and hepatocellular carcinoma [2]
We show that the LDLRϪ/Ϫ mouse is an attractive rodent model to study changes occurring in the liver in NAFLD, and that dietary cholesterol plays an important role in hepatic fat accumulation, inflammation, and fibrosis characteristic of non-alcoholic steatohepatitis (NASH)
Summary
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver disease. To test whether dietary cholesterol can alter the hepatic phenotype in the metabolic syndrome, we fed LDLR؊/؊ mice a high-fat, high-carbohydrate diabetogenic diet (DD) without or with added cholesterol (DDC) Both groups of mice developed obesity and insulin resistance. While triglyceride accumulation is believed to occur initially (the “first hit”), it is postulated that progression to more advanced stages of NAFLD, including inflammation, fibrosis (NASH), and cirrhosis, requires a “second hit” superimposed upon hepatic steatosis. This second hit may include genetic susceptibility, dietary factors, or environmental stressors.
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