Dietary Amino Acid Source Elicits Sex-Specific Metabolic Response to Diet-Induced NAFLD in Mice.

SCOPE: Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, the metabolic and hepatic effects of dietary amino acid (AA) source is assessed in Western diet (WD)-induced NAFLD in male and female mice. METHODS AND RESULTS: The AA source is either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD display glucose intolerance, fasting hyperglycemia, and insulin-resistance and develop NAFLD associated with changes in hepatic gene expression and microbiota dysbiosis. In contrast, males fed the AA-based WD show no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females are protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. CONCLUSIONS: Free dietary AA intake prevents the unhealthy metabolic outcomes of a WD preferentially in male mice.

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism.

Background & Aims: The constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated. Methods: The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle. Results: Although 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline. Conclusions: More than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury. Impact and implications: CAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR.

Pre- and Postnatal Dietary Exposure to a Pesticide Cocktail Disrupts Ovarian Functions in 8-Week-Old Female Mice.

Female infertility has a multifactorial origin, and exposure to contaminants, including pesticides, with endocrine-disrupting properties is considered to be involved in this reproductive disorder, especially when it occurs during early life. Pesticides are present in various facets of the environment, and consumers are exposed to a combination of multiple pesticide residues through food intake. The consequences of such exposure with respect to female fertility are not well known. Therefore, we aimed to assess the impact of pre- and postnatal dietary exposure to a pesticide mixture on folliculogenesis, a crucial process in female reproduction. Mice were exposed to the acceptable daily intake levels of six pesticides in a mixture (boscalid, captan, chlorpyrifos, thiacloprid, thiophanate and ziram) from foetal development until 8 weeks old. Female offspring presented with decreased body weight at weaning, which was maintained at 8 weeks old. This was accompanied by an abnormal ovarian ultrastructure, a drastic decrease in the number of corpora lutea and progesterone levels and an increase in ovary cell proliferation. In conclusion, this study shows that this pesticide mixture that can be commonly found in fruits in Europe, causing endocrine disruption in female mice with pre- and postnatal exposure by disturbing folliculogenesis, mainly in the luteinisation process.

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants.

Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.