Sex-Dependent Gene Regulation in Hepatic Metabolism
Summary
Sex-dependent gene regulation in the liver underpins fundamental differences in nutrient handling, hormone responses and disease susceptibility between males and females. These differences arise from sex-specific patterns of pituitary growth hormone secretion, sex steroid signalling and chromatin modifications that together direct distinct transcriptional programmes. In males, pulsatile growth hormone profiles activate a cohort of male-biased genes via the transcription factor STAT5b, promoting lipid oxidation and drug metabolism. In females, a more continuous growth hormone signal induces female-biased programmes that favour lipid storage and bile acid synthesis. Beyond hormone rhythms, sex differences in epigenetic marks such as histone H3K27-trimethylation establish repressive or permissive chromatin states at regulatory elements, further reinforcing divergent gene networks. Cytochrome P450 enzymes also exhibit sex-specific expression, influencing the synthesis of bioactive lipids and xenobiotic clearance. Together, these layers of regulation shape energy homeostasis, influence the progression of steatosis and fibrosis, and determine the efficacy and toxicity of therapeutics in a sex-specific manner. Understanding these mechanisms is vital for developing precision therapies that account for sex as a biological variable.
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Sex-Dependent Gene Regulation in Hepatic Metabolism publication trend
The graph below shows the total number of articles in sex-dependent gene regulation in hepatic metabolism across all publications each year (not limited to Nature Index journals).
Technical terms
Sexual dimorphism: The distinct patterns of gene expression, physiology and morphology that differ between males and females of a species.
Chromatin state: The structural and chemical configuration of DNA and associated histone proteins that determines accessibility of genes to the transcriptional machinery.
H3K27-trimethylation (H3K27me3): A repressive histone modification catalysed by polycomb repressive complex-2 that silences gene activity by compacting chromatin.
Enhancer: A regulatory DNA element that can increase transcription of target genes by recruiting transcription factors and cofactors over long genomic distances.
Oxylipin: A bioactive lipid derived from the oxygenation of polyunsaturated fatty acids, involved in inflammation and metabolic signalling.
References
- Sexually Dimorphic Effects of CYP2B6 in the Development of Fasting-Mediated Steatosis in Mice: Role of the Oxylipin Products 9-HODE and 9-HOTrE. Biomedicines (2025).
- Feminization of Male Mouse Liver by Persistent Growth Hormone Stimulation: Activation of Sex-Biased Transcriptional Networks and Dynamic Changes in Chromatin States. Molecular and Cellular Biology (2017).
- Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome. PLOS ONE (2016).
- Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2. PLOS Genetics (2020).
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