Insights from a high-fat diet fed mouse model with a humanized liver

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide and is increasing at an alarming rate. NAFLD is strongly associated with obesity and insulin resistance. The use of animal models remains a vital aspect for investigating the molecular mechanisms contributing to metabolic dysregulation and facilitating novel drug target identification. However, some differences exist between mouse and human hepatocyte physiology. Recently, chimeric mice with human liver have been generated, representing a step forward in the development of animal models relevant to human disease. Here we explored the feasibility of using one of these models (cDNA-uPA/SCID) to recapitulate obesity, insulin resistance and NAFLD upon feeding a Western-style diet. Furthermore, given the importance of a proper control diet, we first evaluated whether there are differences between feeding a purified ingredient control diet that matches the composition of the high-fat diet and feeding a grain-based chow diet. We show that mice fed chow have a higher food intake and fed glucose levels than mice that received a low-fat purified ingredient diet, suggesting that the last one represents a better control diet. Upon feeding a high-fat or matched ingredient control diet for 12 weeks, cDNA-uPA/SCID chimeric mice developed extensive macrovesicular steatosis, a feature previously associated with reduced growth hormone action. However, mice were resistant to diet-induced obesity and remained glucose tolerant. Genetic background is fundamental for the development of obesity and insulin resistance. Our data suggests that using a background that favors the development of these traits, such as C57BL/6, may be necessary to establish a humanized mouse model of NAFLD exhibiting the metabolic dysfunction associated with obesity.