Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the US, encompassing a disease spectrum defined by steatosis, inflammation (NASH) , and fibrosis. Although the incidence of NASH is less in women compared with men, the mechanistic basis for this phenomenon is unclear. The aim of this study was to use high-resolution LC-MS/MS proteomics to determine sex-specific differences in liver protein abundance in healthy mice and in response to NASH that may contribute to protection in females. Male and female C57BL6J mice were fed regular chow (RC) or fast food (FF) diet (40% fat, 0.15% cholesterol, 42 g/L high-fructose corn syrup drinking water; n=18-20/g) to induce NASH. Liver weight and steatosis were significantly increased in male and female FF mice compared to RC counterparts, and the effects were more pronounced in males versus females. Plasma insulin and ALT followed similar patterns. Label-free differential mass spectrometry identified 2,917 proteins, where 314 and 445 proteins exhibited statistically significant changes in expression associated with sex and diet, and 2proteins showed a significant sex x diet interaction. Unsupervised hierarchical clustering of the 2proteins identified four groups of proteins defined by sex-specific differences in baseline abundance or response to FF-diet. Enrichment analysis of proteins within the four groups identified biological process related to 1) lipid catabolism and synthesis that were upregulated in FF males compared with females; 2) catabolism and oxidation-reduction reactions that were suppressed by FF diet in males but not females and 3) acyl-CoA hydrolase activity and fatty acid oxidation that were higher in RC females than males and induced by FF in males but not females. These data suggest that sex-specific differences in liver lipid metabolism at baseline and in response to nutritional stress may contribute to sexual dimorphism in NASH susceptibility.

Disclosure

M.Moon: None. A.Murali: None. F.Bello: None. J.Wang: None. M.J.Jurczak: None.

Funding

National Institutes of Health (DK114012)

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