NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk.
NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk.
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DOI：
10.1007/s12325-017-0556-1
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发表时间：
2017-06
影响因子：
3.8
通讯作者：
Lonardo A
中科院分区：
文献类型：
--
作者：
Ballestri S;Nascimbeni F;Baldelli E;Marrazzo A;Romagnoli D;Lonardo A
非酒精性脂肪性肝病（NAFLD）包括脂肪变性、非酒精性脂肪性肝炎、肝硬化和肝细胞癌（HCC），这些疾病与显著的全身性特征和过度的心血管和肝脏相关死亡率相关。NAFLD的发病机制复杂且多因素。内分泌紊乱与代谢异常性状密切相关。例如，在动物和人类研究中，由于年轻个体能够将脂肪酸分配给酮体产生而不是极低密度脂蛋白（VLDL）-三酰甘油，以及白色脂肪组织的性别特异性布朗宁，女性受到保护，免于代谢异常。在实验性过度喂养斑马鱼模型中，卵巢衰老促进了大量肝脏脂肪变性的发展和肝脏疾病的纤维化进展。一致的是，雌激素缺乏，通过增强肝脏炎症变化，加速非酒精性脂肪性肝炎（NASH）的饮食模型中的疾病进展，在卵巢切除小鼠喂食高脂肪饮食。在人类中，NAFLD更常影响男性;绝经前女性同样受到保护，不会发展成NAFLD，因为她们不会患心血管疾病。可以预期，初潮早，肯定与雌激素激活有关，将产生对NAFLD风险的保护作用。然而，有人认为初潮早可能会增加成年后NAFLD的风险，过度肥胖是这种关联的罪魁祸首。生育年龄可能与更严重的肝细胞损伤和炎症有关，但与男性和绝经后状态相比，也与肝纤维化风险降低有关。在以后的生活中，卵巢衰老与重度脂肪变性和纤维化NASH密切相关，这可能发生在绝经后妇女中。雌激素缺乏被认为是通过绝经后代谢综合征的发展而导致这些结果的原因。雌激素补充至少在理论上可以防止NAFLD的发展和进展，正如一些探索激素替代疗法对绝经后妇女的影响的研究所表明的那样，但是不同性激素在NAFLD中的可变影响（即，孕酮的促炎作用）。
Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.