Diabetes and Metabolism Research Unit (R.S., C.S.-L., C.H., D.M.S.), Vall d'Hebron Institut de Recerca, 08035 Barcelona, Universitat Autónoma de Barcelona, 08193 Barcelona, Centro de Investigación Biomédica en Red, 28029 Madrid, Spain Endocrinology and Nutrition Unit (A.L.), Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain; Endocrine, Metabolic and Bariatric Unit (J.M.F.), General Surgery Department, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.
Endocrinology. 2014 Aug;155(8):2820-30. doi: 10.1210/en.2014-1072. Epub 2014 May 14.
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-4α 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-4α. When HNF-4α expression was silenced by using siRNA, adiponectin-induced SHBG overexpression was blocked. Furthermore, adiponectin-induced upregulation of SHBG production via HNF-4α 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-4α 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-4α levels.
流行病学研究表明，男性和女性的血浆 SHBG 水平与血浆脂联素水平相关。目前尚无描述脂联素通过何种分子机制调节肝 SHBG 产生的报道。本研究旨在探讨脂联素是否通过降低肝脂质含量增加 HNF-4α 水平来调节 SHBG 的产生。为此，进行了体外研究（用人 HepG2 细胞进行）和人体肝活检研究。结果表明，脂联素通过激活 HepG2 细胞中的 AMPK 增加 SHBG 的产生。脂联素处理降低了与肝脂肪生成（ACC）相关的酶的 mRNA 和蛋白水平，增加了与脂肪酸氧化（ACOX 和 CPTI）相关的酶的水平。这些肝酶的脂联素诱导变化导致总 TG 和 FFA 减少，HNF-4α 增加。当使用 siRNA 沉默 HNF-4α 表达时，脂联素诱导的 SHBG 过表达被阻断。此外，通过抑制脂肪酸氧化或用 30mM 葡萄糖处理诱导脂肪生成，脂联素诱导的 SHBG 产生通过 HNF-4α 过表达的上调被阻断。最后，脂联素水平与人肝活检中的 HNF-4α 和 SHBG mRNA 水平呈正相关且显著相关。本研究结果首次表明，脂联素通过激活 AMPK 增加 SHBG 的产生，从而降低肝脂质含量并增加 HNF-4α 水平。
