Cherubini Alessandro, Rosso Chiara, Della Torre Sara
Department of Transfusion Medicine, Precision Medicine-Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Medical Sciences, University of Turin, Turin, Italy.
Liver Int. 2025 Mar;45(3):e16088. doi: 10.1111/liv.16088. Epub 2024 Sep 11.
Metabolic dysfunction-associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction-associated steatohepatitis, fibrosis and liver-related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex-specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex-specific role of PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivo models have been developed.
代谢功能障碍相关脂肪性肝病（MASLD，以前称为非酒精性脂肪性肝病，NAFLD）是一种复杂的多因素疾病，通常男性的患病率和严重程度高于女性。在女性方面，男性也更容易发展为代谢功能障碍相关脂肪性肝炎、肝纤维化及肝脏相关并发症。一些遗传、激素、环境和生活方式因素可能导致MASLD在发生、发展和预后方面存在性别差异。然而，绝经后，MASLD的性别特异性患病率在男性和女性之间呈现相反趋势，这表明雌激素信号传导在MASLD的性别二态性中具有重要意义。含帕他汀样磷脂酶结构域蛋白3（PNPLA3）基因编码一种在脂质代谢中起关键作用的三酰甘油脂肪酶，已成为MASLD发病机制中的关键因素，I148M变异与肝脏脂肪含量增加和疾病严重程度密切相关。最近的研究进展表明，携带PNPLA3 I148M变异可能是MASLD的一个危险因素，尤其是对女性而言。为了阐明PNPLA3 I148M在MASLD发生过程中性别特异性作用的分子机制，已经建立了多种体外、离体和体内模型。
