Integrative study of diet-induced mouse models of NAFLD identifies PPAR alpha as a sexually dimorphic drug target

Objective We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Design Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. Results The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor alpha (PPAR alpha) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPAR alpha determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPAR alpha agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPAR alpha. Conclusions These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPAR alpha as a pivotal, sexually dimorphic, pharmacological target.