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

Abstract

ObjectiveWe 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.DesignDifferent 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.ResultsThe 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.ConclusionsThese findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.Trial registration numberNCT02390232.

Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

“…The consequence of its perturbation upon liver steatosis is, however, not yet appreciated and would deserve particular attention. Further in line with this idea, a recent study identified hepatocyte PPARα as a relevant sexually dimorphic target in NAFLD, with potential consequences on therapeutic responses targeting this nuclear receptor [43].…”

Roles of Estrogens in the Healthy and Diseased Oviparous Vertebrate Liver

“…These observations provide evidence that steatosis and hepatocyte rupture represent important pathways controlled by DNA methylation in FLHS chickens [163]. Collectively, these studies on FLHS underscore similarities between this disease in chicken and non-alcoholic fatty liver disease (NAFLD) in mammals, with respect to lipid metabolism, hormonal regulation (sexual dimorphism), and the importance of the PPAR pathways [23,164,165]. However, a major difference is that estrogens appear to promote FLHS in the chicken, while in mammals, they are counteracting the development and progression of NAFLD, which is a metabolic inflammatory-based liver disease with a clear sex-specific male predominance [165,166].…”

“…Collectively, these studies on FLHS underscore similarities between this disease in chicken and non-alcoholic fatty liver disease (NAFLD) in mammals, with respect to lipid metabolism, hormonal regulation (sexual dimorphism), and the importance of the PPAR pathways [23,164,165]. However, a major difference is that estrogens appear to promote FLHS in the chicken, while in mammals, they are counteracting the development and progression of NAFLD, which is a metabolic inflammatory-based liver disease with a clear sex-specific male predominance [165,166]. It is noteworthy that in force-fed palmipedes, such as geese, which develop hepatic steatosis due to repeated high ingestions of a highly caloric diet, the synthesis of triacylglycerols is enhanced by estrogens, but their secretion as VLDL is very efficient and prevents liver steatosis almost completely [167].…”

“…The prevalence of liver diseases is high, and the difference in susceptibility between sexes is still not well understood. Thus, a deep understanding of liver physiology and pathophysiology, in particular of its hormonal component at the molecular level, should help to identify biomarkers for prognostication and better sex-specific treatments in animals and humans for conditions such as metabolic syndrome, NAFLD/NASH, hepatocarcinoma, and the sexually dimorphic immune responses on pathogenesis during Hepatitis B (HBV) and Hepatitis C (HCV) viral infections in which estrogens are implicated [165,[176][177][178][179][180][181].…”

Effects of PPARα pathway on hepatic lipid metabolism in non-alcoholic fatty liver disease rat model

“…The pathological etiology of NAFLD is elusive, while recent evidence hinted that hepatic fat metabolism mediated by PPARα pathway is probable a clue to explaining its mechanism [39,40]. Inhibiting PPARα pathway could restrain gene expression of lipophagy and in ammatory response [41,42].…”