Female C57BL/6 mice exhibit protection against nonalcoholic fatty liver disease and diabesity accompanied by differential regulation of hepatic lipocalin prostaglandin D2 synthase.

Nonalcoholic fatty liver disease (NAFLD) and its development into nonalcoholic steatohepatitis (NASH) are challenging health concerns globally. Clinically, the prevalence and severity of NAFLD/NASH are higher in men than in premenopausal women. NAFLD is strongly correlated with obesity, both of which are tied to high-fat/fructose-rich western diets. Therefore, we aimed to investigate sexual dimorphism in NAFLD pathogenesis in male and female C57BL/6 mice fed different diets. Male and female C57BL/67 mice were divided into four groups and kept on a chow (C), chow plus high fructose (CF), high fat (HF), and high fat plus high fructose (HFF) diet for 22 weeks. Liver tissues were collected at the end of the study and processed for NAFLD/NASH-related histology (H&E and trichrome staining), protein expression (SREBP1, SCAP, FABP4, α-SMA, TGF-β and L-PGDS), and biochemical parameters measurement. Our results displayed that female mice exhibited protection against NAFLD and diabesity on HF and HFF diets compared to male mice fed similar diets. Additionally, female mice showed protection from fibrosis compared to male mice. Both male and female mice fed HF and HFF diet groups displayed the cytosol-to-nuclear translocation of Lipocalin Prostaglandin D2 Synthase (L-PGDS). Cytoplasmic levels of L-PGDS were absent in females compared to low levels in males, revealing a possible sex-specific mechanism tied to fructose and fat metabolism. Collectively, female mice showed protection against NAFLD and diabesity relative to male mice, accompanied by differential regulation of hepatic lipocalin prostaglandin D2 synthase.