Alternative human cell-based models of fatty liver disease

DESCRIPTION (provided by applicant): Obesity and Type 2 diabetes affect the lives of millions of people worldwide, add significantly to health-related expenditures, and are seemingly unmanageable health issues, since rates of occurrence are steadily increasing. In parallel with the increasing incidence of obesity and insulin resistance, is the occurrence of non-alcoholic fatty liver disease (NAFLD), a chronic hepatic disorder affecting up to 25% of the general population; including a significant portion of pediatric cases. Several intracellular events leading to NAFLD and progression to non-alcoholic steatohepatitis (NASH) have been identified. However, the exact molecular mechanisms require further investigation, especially in human systems. Primary human hepatocytes are the most physiologically relevant cell-based model for in vitro hepatic function. However, the availability of primary human hepatocytes for cell-based applications is significantly limited. Additional confounding factors for the use of primary human hepatocytes include poor recovery from cryopreservation, rapid loss of functional characteristics, and a short lifespan in culture. Available hepatoma cell lines do not express many of the proteins necessary for the study of hepatocyte function. Additionally, freshly isolated rodent hepatocytes display similar problems as human hepatocytes in culture, and they do not faithfully recapitulate observations in human hepatocytes. In order to address the market demand for relevant human cell-based models of hepatocyte function, we have developed an alternative model based upon the differentiation of adipose tissue derived adult stem cells (ASC) to hepatocyte-like cells. We have obtained significant preliminary data suggesting that the ASC-derived hepatocytes possess many of the characteristics of primary human hepatocytes and are in the process of developing applications of these cells for use in cell therapy and drug development. As an additional alternative model, we will employ a recently developed hepatocyte-like cell line, HepaRG, which is derived from progenitor cells isolated from a human liver tumor. It is the goal of this proposal to provide proof-of-concept for the use of the ASC-derived hepatocytes and/or HepaRG as a model system(s) for NAFLD. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disorder affecting up to 25% of the general population and can progress to non-alcoholic steatohepatitis (NASH) and liver failure. Current NAFLD models are grossly inadequate due to the limited availability and poor characteristics of human primary hepatocytes in culture. This proposal focuses on the characterization of two alternative human cell-based models for the study of NAFLD in vitro, the development and implementation of which will have a significant and immediate impact on the study of NAFLD in humans.