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Sex differences in murine MASH induced by a fructose-palmitate-cholesterol-enriched diet
Lakshmi Arivazhagan1, Sofie Delbare2, Robin A Wilson1
1Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine Langone Health, New York, NY 10016, USA.
JHEP Reports : Innovation in Hepatology
|February 6, 2025
Summary
Female mice exhibit more severe metabolic syndrome-associated steatohepatitis (MASH) than males when fed a fructose-rich diet. Sex-specific molecular differences in liver cells were observed, highlighting the need for sex-inclusive MASH research.
Area of Science:
- Hepatology
- Metabolic Diseases
- Molecular Biology
Background:
- Metabolic syndrome-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) affect over 25% and 3-6% of the global population, respectively.
- High-fructose corn syrup consumption is linked to metabolic and hepatic issues, but sex-specific effects on MASLD/MASH are understudied.
Purpose of the Study:
- To investigate sex-dependent responses to fructose-containing diets in a mouse model of MASH.
- To identify molecular differences in liver cells between male and female mice fed a NASH diet supplemented with fructose.
Main Methods:
- Female and male C57BL/6J mice were fed a fructose-palmitate-cholesterol (FPC)-NASH diet or standard chow for 16 weeks.
- Liver tissue underwent single-nucleus RNA sequencing; plasma and publicly available human MASH data were also analyzed.
Main Results:
- The FPC-NASH diet induced metabolic dysfunction in both sexes, with females showing significantly higher steatosis, inflammation, and fibrosis.
- Sex-specific transcriptional profiles were identified in hepatocytes and stellate cells, with enriched lipid metabolism pathways in females.
- Reduced bile acid metabolism was observed in female mice and human hepatocytes under FPC-NASH/MASH conditions compared to males.
Conclusions:
- Significant sex differences in diet-induced liver disease were observed in mice, mirroring findings in human MASH.
- Intrinsic, sex-specific, diet-dependent molecular disparities exist, emphasizing the need for sex-inclusive studies in MASLD/MASH research.
