Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a clinicopathologic spectrum of diseases ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease that may progress to cirrhosis and cirrhosis-related complications, including hepatocellular carcinoma. The prevalence of NAFLD, including NASH, is also increasing in parallel with the growing epidemics of obesity and diabetes. However, the causal relationships between obesity and/or diabetes and NASH or liver tumorigenesis have not yet been clearly elucidated. Animal models of NAFLD/NASH provide crucial information, not only for elucidating the pathogenesis of NAFLD/NASH, but also for examining therapeutic effects of various agents. A high-fat diet is widely used to produce hepatic steatosis and NASH in experimental animals. Several studies, including our own, have shown that long-term high-fat diet loading, which can induce obesity and insulin resistance, can also induce NASH and liver tumorigenesis in C57BL/6J mice. In this article, we discuss the pathophysiology of and treatment strategies for NAFLD and subsequent NAFLD-related complications such as NASH and liver tumorigenesis, mainly based on lessons learned from mouse models of high-fat diet-induced NAFLD/NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is histologically characterized by more than 5% hepatic triglyceride accumulation, resulting in steatosis and hepatic inflammation [1]
NAFLD encompasses a clinicopathologic spectrum of diseases ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), the more aggressive form of fatty liver disease that may progress to cirrhosis and cirrhosis-related complications, including hepatocellular carcinoma (HCC)
The proportion of nodular lesions was significantly lower in the Irs1−/− mice fed the HF diet than in the WT mice fed the same diet (9.1% in the Irs1−/− mice vs. 63.6% in the WT mice). These results indicate that the disruption of Irs1 protected against HF diet-induced NASH and liver tumorigenesis despite being associated with severe hyperglycemia and insulin resistance [26]
Summary
Nonalcoholic fatty liver disease (NAFLD) is histologically characterized by more than 5% hepatic triglyceride accumulation, resulting in steatosis and hepatic inflammation [1]. We demonstrated that WT mice fed a HF diet maintained near-normal glucose tolerance, whereas mice with haploinsufficiency of beta cell-specific glucokinase (Gck+/−) developed diabetes because of insufficient beta cell hyperplasia, despite the two groups of animals showing a similar degree of insulin resistance [43,44,45]. Johnson et al advocated the hypothesis that hyperinsulinemia, but not hyperglycemia, is causally linked to an increased cancer risk [48], and our results support their hypothesis
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