Adiponectin Upregulates SHBG Production: Molecular Mechanisms and Potential Implications
Adiponectin Upregulates SHBG Production: Molecular Mechanisms and Potential Implications
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DOI：
10.1210/en.2014-1072
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发表时间：
2014-08-01
期刊：
影响因子：
4.8
通讯作者：
Selva, David M.
中科院分区：
文献类型：
--
作者：
Simo, Rafael;Saez-Lopez, Cristina;Selva, David M.
流行病学研究表明，男性和女性血浆SHBG水平与血浆脂联素水平相关。没有关于脂联素调节肝脏SHBG产生的分子机制的报道。本研究的目的是探讨脂联素是否通过降低肝脏脂质含量，通过增加HNF-4 α水平来调节SHBG的产生。为此，使用人HepG2细胞进行了体外研究，并进行了人肝活检。我们的研究结果表明，脂联素处理通过AMPK激活HepG2细胞增加SHBG的产生。脂联素处理降低了肝脏脂肪生成相关酶（ACC）的mRNA和蛋白水平，升高了脂肪酸氧化相关酶（ACOX和CPTI）的mRNA和蛋白水平。这些脂联素引起的肝酶变化导致总TG和FFA的减少和HNF-4 α的增加。当使用siRNA沉默HNF-4 α表达时，脂联素诱导的SHBG过表达被阻断。此外，脂联素通过HNF-4 α过表达诱导的SHBG产生上调被抑制脂肪酸氧化或在HepG2细胞中通过30mM葡萄糖处理诱导脂肪生成所消除。最后，在人类肝脏活检中，脂联素水平与HNF-4 α和SHBG mRNA水平呈正相关。我们的研究结果首次表明，脂联素通过激活AMPK来增加SHBG的产生，从而降低肝脏脂质含量并增加HNF-4 α水平。
Epidemiological studies have shown that plasma SHBG levels correlate with plasma adiponectin levels, both in men and women. There are no reports describing any molecular mechanism by which adiponectin regulates hepatic SHBG production. The aim of the present study is to explore whether adiponectin regulates SHBG production by increasing HNF-4 alpha levels through reducing hepatic lipid content. For this purpose, in vitro studies using human HepG2 cells, as well as human liver biopsies, were performed. Our results show that adiponectin treatment increased SHBG production via AMPK activation in HepG2 cells. Adiponectin treatment decreased the mRNA and protein levels of enzymes related to hepatic lipogenesis (ACC) and increased those related to fatty acid oxidation (ACOX and CPTI). These adiponectin-induced changes in hepatic enzymes resulted in a reduction of total TG and FFA and an increase of HNF-4 alpha. When HNF-4 alpha expression was silenced by using siRNA, adiponectin-induced SHBG overexpression was blocked. Furthermore, adiponectin-induced upregulation of SHBG production via HNF-4 alpha overexpression was abrogated by the inhibition of fatty acid oxidation or by the induction of lipogenesis with a 30mM glucose treatment in HepG2 cells. Finally, adiponectin levels correlated positively and significantly with both HNF-4 alpha and SHBG mRNA levels in human liver biopsies. Our results suggest for the first time that adiponectin increases SHBG production by activating AMPK, which reduces hepatic lipid content and increases HNF-4 alpha levels.