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; however, the mechanisms by which chronic lipid and cholesterol overload increase female susceptibility remain unclear. Male and female mice were fed either control or high-fat, high-cholesterol (HFHC) diets for 40 weeks. Analyses included liver histology, bile acid (BA) profiling in serum, bile, and colonic contents, hepatic transcriptomics, fecal 16S rRNA sequencing, and integrated association analyses. Human obese liver transcriptomes were used for cross species validation. HFHC feeding caused steatohepatitis in both sexes, whereas female mice showed higher biliary cholesterol saturation and more frequent hepatocellular cholestasis. Female HFHC mice also exhibited higher colonic deoxycholic acid (DCA) levels and BA hydrophobicity. HFHC feeding altered genus-level gut microbial composition and predicted BA-related functions, and differential genera were associated with colonic DCA and BA hydrophobicity. Hepatic transcriptomics indicated stronger cholesterol core metabolism, cholesterol transport and excretion, biliary cholesterol efflux-related signatures, and increased Srebf2 activity in female HFHC mice. In contrast, male HFHC mice maintained relatively stronger hydrophilic BA conversion, Ppara activity, fatty acid oxidation, and safe lipid storage signatures. Human obese liver transcriptomes supported higher cholesterol metabolic activity and increased SREBF2 and HNF4A activity in women. In conclusion, long-term HFHC feeding promotes a female-biased pre-lithogenic state characterized by increased biliary cholesterol saturation, stronger hepatic cholesterol handling, and gut microbiota-associated changes in colonic BA composition.
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