Challenging the Rodent Hegemony: A New Rabbit Model of Nonalcoholic Steatohepatitis

Abstract

Since its initial description in 1980, nonalcoholic fatty liver disease (NAFLD) has become an increasingly important public health problem.1 It is projected that NAFLD will replace hepatitis C as the most common indication for liver transplantation in the United States within the next 20 years.2 Increasingly, NAFLD is being recognized as a problem not only in the developed countries but worldwide.3 A strong association with metabolic syndrome and the increasing prevalence of NAFLD has paralleled the rising epidemics of obesity, insulin resistance, and diabetes mellitus.4 While important advances have been made in understanding the pathogenesis of NAFLD, the precise molecular events that lead to its development remain elusive. Among the crucial challenges faced is the difficulty in differentiating the presence of fat in the liver (simple steatosis) from fat associated with hepatocellular injury, inflammation, and fibrosis (steatohepatitis, NASH). The latter condition is associated with progressive fibrosis that can ultimately lead to cirrhosis, with further complications of portal hypertension and hepatocellular carcinoma.5 It is very difficult to investigate the molecular pathogenesis of NAFLD and NASH in humans because of the heterogeneity of human populations and wide differences in their diet and lifestyle. More importantly, the inability to obtain multiple liver biopsies from patients with NAFLD or NASH and healthy volunteers adds to the difficulty of these studies. Given these technical issues and associated ethical challenges involved in studying patients with NAFLD, considerable effort has been expended to develop animal models of fatty liver disease. In this issue of the American Journal of Pathology, Ogawa et al6 report another animal model of NAFLD, which utilizes rabbits fed a high-fat diet, resulting in the development of progressive liver fibrosis and hepatic cholesterol accumulation.