Biological Sex Modifies the Link Between Nutrient Intake and MASLD: Intrinsic Oxidative Vulnerability in Females
Alina Khusnullina, Hisanori Goto, Kumi Kimura, Alisa Arslanova, Hiroaki Takayama, Yujiro Nakano, Yumie Takeshita, Hiromasa Tsujiguchi, Akinori Hara, Hiroyuki Nakamura, Kenichi Harada, Yasuhiko Yamamoto, Toshinari TakamuraAbstract
Purpose
Whether biological sex modifies the association between diet and liver disease remains unclear. We applied a reverse-translational strategy linking sex-stratified population data with mechanistic studies in a murine model.
Methods
We analyzed associations between dietary nutrients and hepatic steatosis in a community-based Japanese cohort (the Shika study). Based on the human findings, mice were fed a Western diet with fructose–sucrose–supplemented water to investigate sex-dependent mechanisms.
Results
In the Shika study, steatosis in women—but not in men—was associated with higher dietary cholesterol/fat density and with a higher sucrose-to-total carbohydrate ratio. Modeling this risk in mice revealed a dissociation between systemic metabolism and liver pathology: despite exhibiting milder systemic obesity than males, females developed more pronounced fibrosis and oxidative injury. Transcriptomic analysis identified distinct sex-biased pathways. Males preferentially upregulated genes involved in glutathione metabolism (e.g., Gst, Gpx). In contrast, females exhibited higher expression of genes associated with microsomal ω-oxidation and acyl-CoA hydrolysis (e.g., Cyp4a, Acot), accompanied by marked oxidative stress and a Kupffer cell–skewed inflammatory signature.
Conclusions
By integrating sex-stratified epidemiological evidence in humans with the intrinsic oxidative vulnerability identified in mice, our findings highlight biological sex as a critical modifier of nutrition-driven liver injury. These findings suggest that rigorous nutritional management is particularly important for preventing disease progression in women with metabolic dysfunction-associated steatotic liver disease (MASLD).