title: Sex Hormone-Binding Globulin Reduction in Metabolic Disorders May Play a Role in NAFLD Development.
abstract: 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 PPARγ 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.
authors.affiliation: Diabetes and Metabolism Research Unit, Vall Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saez-Lopez
authors.affiliation: Diabetes and Metabolism Research Unit, Vall Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Barbosa-Desongles
authors.affiliation: Diabetes and Metabolism Research Unit, Vall Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Child and Family Research Institute, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Dyer
authors.affiliation: Child and Family Research Institute, Department of Paediatrics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Innis
authors.affiliation: Diabetes and Metabolism Research Unit, Vall Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Simó
authors.affiliation: Diabetes and Metabolism Research Unit, Vall Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona and CIBERDEM (ISCIII), Barcelona, Spain.
authors.forename: David M
authors.initials: DM
authors.lastname: Selva
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005260:Female; D005632:Fructose / Q000009:adverse effects; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*
chemical_list: D047495:PPAR gamma; D012738:Sex Hormone-Binding Globulin; D005632:Fructose