Apolipoprotein (apo) C1 mice as a model of nonalcoholic fatty liver disease

Liver injury develops in heterozygous, human apolipoprotein (apo) C1 overexpressing mice with age. This observation was first made in these mice at 8-10 and was found to worsen by 20-22 months of age in the laboratory of Dr. Harshini V. deSilva. ApoC1 mice have been documented to have combined hyperlipidemia (elevated levels of plasma cholesterol and triglycerides). They have also been observed to have altered hepatic microcirculation and tissue injury characteristic of nonalcoholic fatty liver disease (NAFLD). NAFLD is currently the predominant cause of liver injury in the Western world in individuals who do not drink significant quantities of alcohol or have viral hepatitis. The increasing prevalence of this disease is due to its strong association with hyperlipidemia and obesity. This disease can evolve in varying degrees from simple steatosis (lipid accumulation in the liver) to cirrhosis and hepatocellular carcinoma. The major aims of this study were to (1) characterize the liver injury during aging in this model and (2) to use caloric restriction as an intervention to delay or prevent NAFLD. A model for liver disease in the apoC1 mice was proposed based on published data about the progression of NAFLD and observations in our laboratory. In this study it was determined that apoC1 mice 10-12 months of age have heterogeneous sinusoidal architecture, increased inflammatory infiltrate and focal necrosis as compared with normal age-matched littermates. These observations are consistent with what has been observed histologically for steatohepatitis, the inflammatory stage of NAFLD. The data suggest that inflammation may play a major role in the progression of this disease. Thirty percent caloric restriction effectively attenuated the development of disease in the apoC1 mice. The level of combined hyperlipidemia was contained, and the age-associated progression of liver injury in these animals was minimized.