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

Area of Science:

• Hepatology
• Metabolic disease research
• Animal modeling

Background:

• Non-alcoholic fatty liver disease (NAFLD) is a global health concern linked to obesity and insulin resistance.
• Animal models are essential for understanding NAFLD pathogenesis and identifying drug targets.
• Humanized mouse models offer improved physiological relevance compared to traditional models.

Purpose of the Study:

• To assess the utility of cDNA-uPA/SCID chimeric mice for modeling diet-induced obesity, insulin resistance, and NAFLD.
• To compare a purified ingredient control diet with a standard chow diet for NAFLD research.
• To investigate the impact of genetic background on metabolic dysfunction in humanized mice.

Main Methods:

• Feeding cDNA-uPA/SCID chimeric mice a Western-style diet or a matched control diet for 12 weeks.
• Evaluating diet-induced changes in food intake, glucose levels, body weight, and liver steatosis.
• Comparing the efficacy of a purified ingredient control diet versus a grain-based chow diet.

Main Results:

• The purified ingredient control diet resulted in lower food intake and fed glucose levels compared to chow.
• Chimeric mice developed significant macrovesicular steatosis on the high-fat diet but resisted obesity and maintained glucose tolerance.
• Genetic background significantly influences the development of obesity and insulin resistance.

Conclusions:

• cDNA-uPA/SCID chimeric mice develop NAFLD but not obesity or insulin resistance on a Western diet, indicating limitations in current models.
• A purified ingredient diet is a more suitable control for high-fat diet studies in this model.
• Utilizing a susceptible genetic background, like C57BL/6, may be necessary to fully recapitulate metabolic dysfunction in humanized NAFLD models.