Sex Hormone-Binding Globulin Reduction in Metabolic Disorders May Play a Role in NAFLD Development
Sex Hormone-Binding Globulin Reduction in Metabolic Disorders May Play a Role in NAFLD Development
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DOI：
10.1210/en.2016-1668
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发表时间：
2017-03-01
期刊：
影响因子：
4.8
通讯作者：
Selva, David M.
中科院分区：
文献类型：
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作者：
Saez-Lopez, Cristina;Barbosa-Desongles, Anna;Selva, David M.
低血浆性激素结合球蛋白（SHBG）水平是慢性代谢性疾病的标志，包括非酒精性脂肪性肝病（NAFLD）， NAFLD代表了从肝细胞脂肪变性到脂肪性肝炎到纤维化和不可逆肝硬化的一系列疾病。SHBG生成改变与NAFLD发展和进展之间的功能联系尚不清楚。我们研究了过表达人SHBG对2种NAFLD小鼠模型的影响：基因诱导的双转基因小鼠和饮食诱导的模型。值得注意的是，在两种NAFLD模型中，SHBG的过表达通过降低关键的脂肪生成酶显著减少了肝脏脂肪的积累。通过调节SHBG表达和在HepG2细胞中添加外源性SHBG，这些发现得到了证实，表明其机制具有细胞自主性质。机制上，外源性SHBG处理通过激活细胞外信号调节激酶-1/2丝裂原活化蛋白激酶途径，通过降低PPAR γ信使RNA和蛋白水平，下调关键的脂肪生成酶。综上所述，我们发现SHBG调节肝脏脂肪生成。这一点很重要，因为肥胖和2型糖尿病患者SHBG血浆水平的降低可能通过增加肝脏脂肪生成与NAFLD的发展直接相关。我们的结果表明SHBG是预防或阻止NAFLD发展的治疗靶点。
Low plasma sex hormone-binding globulin (SHBG) levels are a hallmark in chronic metabolic diseases, including nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The functional link between altered SHBG production and NAFLD development and progression remains unclear. We investigated the effects of overexpressing human SHBG in 2 mouse models of NAFLD: a genetically induced double transgenic mouse and a diet-induced model. Remarkably, SHBG overexpression in both NAFLD models significantly reduced liver fat accumulation by reducing key lipogenic enzymes. These findings were corroborated by modulating SHBG expression and by adding exogenous SHBG in HepG2 cells, suggesting the cell autonomous nature of the mechanism. Mechanistically, exogenous SHBG treatment downregulated key lipogenic enzymes by reducing PPAR gamma messenger RNA and protein levels through activation of extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase pathway. Taking together, we found that SHBG modulates hepatic lipogenesis. This is of importance because reduction of SHBG plasma levels in obese and type 2 diabetic subjects could be directly associated with NAFLD development through an increase in hepatic lipogenesis. Our results point to SHBG as a therapeutic target for preventing or arresting NAFLD development.