Department of Health Sciences, University of Milan, 20146 Milan, Italy.
Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy.
Nutrients. 2022 Aug 10;14(16):3262. doi: 10.3390/nu14163262.
Non-alcoholic fatty liver disease (NAFLD) represents a public health issue, due to its prevalence and association with other cardiometabolic diseases. Growing evidence suggests that NAFLD alters the production of hepatokines, which, in turn, influence several metabolic processes. Despite accumulating evidence on the major role of estrogen signaling in the sexually dimorphic nature of NAFLD, dependency of hepatokine expression on sex and estrogens has been poorly investigated. Through in vitro and in vivo analysis, we determined the extent to which hepatokines, known to be altered in NAFLD, can be regulated, in a sex-specific fashion, under different hormonal and nutritional conditions. Our study identified four hepatokines that better recapitulate sex and estrogen dependency. Among them, adropin resulted as one that displays a sex-specific and estrogen receptor alpha (ERα)-dependent regulation in the liver of mice under an excess of dietary lipids (high-fat diet, HFD). Under HFD conditions, the hepatic induction of adropin negatively correlates with the expression of lipogenic genes and with fatty liver in female mice, an effect that depends upon hepatic ERα. Our findings support the idea that ERα-mediated induction of adropin might represent a potential approach to limit or prevent NAFLD.
非酒精性脂肪性肝病（NAFLD）是一个公共健康问题，因为其发病率高且与其他心血管代谢疾病相关。越来越多的证据表明，NAFLD 改变了肝细胞因子的产生，而这些因子反过来又影响了许多代谢过程。尽管有越来越多的证据表明雌激素信号在 NAFLD 的性别二态性中起着重要作用，但肝细胞因子表达对性别和雌激素的依赖性尚未得到充分研究。通过体外和体内分析，我们确定了在不同激素和营养条件下，已知在 NAFLD 中发生改变的肝细胞因子在多大程度上可以以性别特异性的方式进行调节。我们的研究确定了四种肝细胞因子，它们可以更好地再现性别和雌激素依赖性。其中，adropin 是一种在饮食脂质过量（高脂肪饮食，HFD）下的小鼠肝脏中以性别特异性和雌激素受体 alpha（ERα）依赖性方式进行调节的细胞因子。在 HFD 条件下，adropin 在肝脏中的诱导与脂肪生成基因的表达和雌性小鼠的脂肪肝呈负相关，这种作用依赖于肝 ERα。我们的发现支持这样一种观点，即 ERα 介导的 adropin 诱导可能代表一种限制或预防 NAFLD 的潜在方法。
