Sex Differences in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma. Epidemiological evidence shows that premenopausal women are relatively protected against NAFLD compared with men, but this advantage diminishes after menopause, implicating a key role for oestrogens. Sex differences arise from distinct hormonal milieus, gene–environment interactions and differential expression of metabolic and inflammatory pathways. In women, oestrogen receptor-α (ER-α) modulates lipid handling, glucose metabolism and antioxidant responses, attenuating lipid droplet accumulation and oxidative stress. In men, androgen signalling influences insulin sensitivity and lipid synthesis, contributing to a generally higher prevalence of steatosis at younger ages. Genetic factors, notably the PNPLA3 p.I148M variant, interact with sex hormones to amplify risk, particularly in women approaching or beyond menopause. Metabolomic and transcriptomic studies reveal sex-biased pathways of amino acid utilisation, lipid oxidation and inflammatory signalling. Clinically, sex differences affect diagnostic thresholds, the performance of imaging modalities and the trajectory towards fibrosis and cirrhosis. A clearer understanding of these distinctions is critical to tailor screening strategies, preventive interventions and emerging therapies according to sex and hormonal status.

Research from Nature Portfolio

Recent studies have illuminated the interplay between sex hormones and genetic variants in driving NAFLD susceptibility. One investigation demonstrated that women carrying the PNPLA3 p.I148M variant exhibit a multiplicative increase in liver fat content and fibrosis markers, linked to oestrogen-driven upregulation of PNPLA3 via ER-α binding to a novel enhancer element. Functional assays in hepatocyte organoids confirmed that ER-α agonists induce variant expression, promoting lipid droplet formation and stellate-cell activation. A foundational mouse model study has further revealed that hepatic ER-α is indispensable for regulating gluconeogenic genes and lipogenic enzymes in males. Mice lacking liver ER-α develop fasting hyperglycaemia, elevated hepatic triglycerides and increased expression of fatty acid synthase and acetyl-CoA carboxylase, underscoring a conserved role for oestrogen signalling in male liver energy homeostasis.

Sex Differences in Nonalcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in sex differences in nonalcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Nonalcoholic fatty liver disease (NAFLD): Chronic liver condition characterised by excessive hepatic lipid accumulation in individuals who consume little or no alcohol.

Hepatic steatosis: Accumulation of triglyceride-rich lipid droplets within hepatocytes, the hallmark of early NAFLD.

Fibrosis: Progressive deposition of extracellular matrix in the liver, leading to architectural distortion and functional impairment.

Oestrogen receptor-α (ER-α): Nuclear hormone receptor that mediates the transcriptional effects of oestrogens on metabolic and inflammatory genes in the liver.

PNPLA3 p.I148M variant: Single amino acid substitution in patatin-like phospholipase domain-containing protein 3 associated with increased hepatic fat content and fibrosis susceptibility.

References

1. Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nature Medicine (2023).
2. Influence of age, body mass index and gender on sonographic indicators of the liver in patients with metabolic dysfunction-associated steatotic liver disease. Gastroenterology (2024).
3. Estrogen-dependent activation of TRX2 reverses oxidative stress and metabolic dysfunction associated with steatotic disease. Cell Death & Disease (2025).
4. Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males. Scientific Reports (2017).
5. Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver. Cell Metabolism (2018).
6. Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat[S]. Journal of Lipid Research (2012).