Sex differences in hepatic cholesterol handling and colonic bile acid profiles underlie gallstone susceptibility after high-fat, high-cholesterol feeding
Sex and obesity are major risk factors for cholesterol gallstone disease, but how chronic lipid and cholesterol overload promotes female susceptibility remains unclear. Male and female mice were fed control or high-fat, high-cholesterol (HFHC) diets for 40 weeks. Liver histology, bile acid (BAs) profiling in serum, bile, and colonic contents, hepatic RNA-seq, pathway enrichment, transcription factor activity, and cross-omics associations were analyzed. Human obese liver transcriptomes were used for directional validation. HFHC feeding induced steatohepatitis including liver injury and increased cholestatic injury scores, especially in female mice. BAs profiling showed compartment-specific changes, with female HFHC mice showing higher colonic DCA and hydrophobic BAs enrichment. Hepatic transcriptomics indicated stronger cholesterol core metabolism, cholesterol transport/excretion, biliary cholesterol efflux-related signatures, and Srebf2 activity in female HFHC mice. In contrast, male HFHC mice retained relatively stronger hydrophilic BAs conversion, Ppara activity, fatty acid oxidation, and safe lipid storage signatures. Colonic DCA was associated with biliary cholesterol saturation, and FXR-related features were linked to intestinal BAs hydrophobicity. Human obese liver transcriptomes supported higher cholesterol metabolic activity and Srebf2/Hnf4a activity in women. In conclusion, long-term HFHC feeding promotes a female-biased pre-lithogenic state characterized by enhanced biliary cholesterol handling and colonic hydrophobic BAs enrichment, highlighting enterohepatic cholesterol-BAs alterations as a metabolic basis for female gallstone susceptibility.
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