Adiponectin upregulates SHBG production: molecular mechanisms and potential implications.
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.
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.
Rafael
R
Simó
Cristina
C
Saez-Lopez
Albert
A
Lecube
Cristina
C
Hernandez
Jose Manuel
JM
Fort
David M
DM
Selva
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000737:chemistry* / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism; D010084:Oxidation-Reduction; D012738:Sex Hormone-Binding Globulin / Q000096:biosynthesis* / Q000737:chemistry* / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
C499918:ADIPOQ protein, human; D052242:Adiponectin; D005227:Fatty Acids; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D012738:Sex Hormone-Binding Globulin; D055372:AMP-Activated Protein Kinases