Sex-specific effects of PNPLA3 I148M

Metabolic dysfunction–associated steatotic liver disease (MASLD, previously termedNAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease show-ing generally higher prevalence and severity in men than in women. With respectto women, men are also more prone to develop metabolic dysfunction–associatedsteatohepatitis, fibrosis and liver-related complications. Several genetic, hormonal,environmental and lifestyle factors may contribute to sex differences in MASLD de-velopment, progression and outcomes. However, after menopause, the sex-specificprevalence of MASLD shows an opposite trend between men and women, pointingto the relevance of oestrogen signalling in the sexual dimorphism of MASLD. Thepatatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, that encodesa triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as akey player in the pathogenesis of MASLD, with the I148M variant being strongly asso-ciated with increased liver fat content and disease severity. Recent advances indicatethat carrying the PNPLA3 I148M variant can be a risk factor for MASLD especiallyfor women. To elucidate the molecular mechanisms underlying the sex-specific roleof PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivomodels have been developed.