Faculty, Staff and Student Publications
Language
English
Publication Date
12-29-2025
Journal
eLife
DOI
10.7554/eLife.96783
PMID
41460563
PMCID
PMC12747522
PubMedCentral® Posted Date
12-29-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate with survival outcomes for HCC patients. Gene signatures unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes and promotes liver tumorigenesis in females that, intriguingly, coincides with increased serum bile acid (BA) levels. Despite similar genetics, knockout male mice displayed higher serum BA concentrations, while female knockouts excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC.
Keywords
Male, Female, Animals, Mice, Liver Neoplasms, Experimental, Sex Factors, Carcinoma, Hepatocellular, Bile Acids and Salts, Homeostasis, Liver, Incidence, Transcriptome, Protective Factors, Mice, Knockout, Mice, Inbred C57BL, Sex Characteristics
Published Open-Access
yes
Recommended Citation
Patton, Megan E; Kelekar, Sherwin; Taylor, Lauren J; et al., "Sex Differences in Bile Acid Homeostasis and Excretion Underlie the Disparity in Liver Cancer Incidence Between Males and Females" (2025). Faculty, Staff and Student Publications. 6060.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6060
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