Feasibility of a Novel Nonhuman Primate Model of Age-Related Nonalcoholic Fatty Liver Disease

Abstract

The objective of the proposed study is to investigate the feasibility of the marmoset as an animal model to study age-associated nonalcoholic fatty liver disease (NAFLD). This chronic liver disease includes a spectrum of disorders ranging from increased triglyceride accumulation in the liver or hepatic steatosis to the more severe inflammatory form nonalcoholic steatohepatitis that can lead to cirrhosis and even hepatocellular carcinoma in individuals who do not have a history of alcohol abuse. Aging increases the prevalence of NAFLD and is strongly associated with the progression and severity of this disease. End-stage hepatic failure and liver cancer resulting from advanced NAFLD are leading indications for liver transplantation enhancing the burden on our healthcare systems. Accumulating clinical evidence also suggests that patients with NAFLD have a higher prevalence of cardiovascular disease. Pathogenetic mechanisms involved in the development and progression of NAFLD are poorly understood and as such, there is a lack of effective therapies. The common marmoset is a relatively short-lived non-human primate that recapitulates many of the physiological changes that occur in human aging. We hypothesized an age-associated increase in hepatic steatosis and alterations in serum lipid profile in the marmoset model. An increase in triglyceride levels and oil red o staining in liver tissues of old marmosets compared to young animals was observed suggesting an age-associated increase in hepatic steatosis in marmosets as observed in humans. Lipidomic studies were also performed using blood samples from male and female marmosets to investigate age-associated changes in specific lipid species, which are characteristic of aberrant lipid metabolism. Analysis of the results revealed significant decreases in several phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin species in the plasma of old marmosets compared to young marmosets. We are now performing studies to determine whether the observed changes in different lipid species could influence the development of cardiovascular disease and provide new insights underlying the mechanisms of NAFLD development with aging.