Integrative study of diet-induced mouse models of NAFLD identifies PPARα 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 α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. CONCLUSIONS: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. TRIAL REGISTRATION NUMBER: NCT02390232.

Insights into the role of hepatocyte PPARα activity in response to fasting.

The liver plays a central role in the regulation of fatty acid metabolism. Hepatocytes are highly sensitive to nutrients and hormones that drive extensive transcriptional responses. Nuclear hormone receptors are key transcription factors involved in this process. Among these factors, PPARα is a critical regulator of hepatic lipid catabolism during fasting. This study aimed to analyse the wide array of hepatic PPARα-dependent transcriptional responses during fasting. We compared gene expression in male mice with a hepatocyte specific deletion of PPARα and their wild-type littermates in the fed (ad libitum) and 24-h fasted states. Liver samples were acquired, and transcriptome and lipidome analyses were performed. Our data extended and confirmed the critical role of hepatocyte PPARα as a central for regulator of gene expression during starvation. Interestingly, we identified novel PPARα-sensitive genes, including Cxcl-10, Rab30, and Krt23. We also found that liver phospholipid remodelling was a novel fasting-sensitive pathway regulated by PPARα. These results may contribute to investigations on transcriptional control in hepatic physiology and underscore the clinical relevance of drugs that target PPARα in liver pathologies, such as non-alcoholic fatty liver disease.