title: Hepatic transforming growth factor-β 1 stimulated clone-22 D1 controls systemic cholesterol metabolism.
abstract: Disturbances in lipid homeostasis are hallmarks of severe metabolic disorders and their long-term complications, including obesity, diabetes, and atherosclerosis. Whereas elevation of triglyceride (TG)-rich very-low-density lipoproteins (VLDL) has been identified as a risk factor for cardiovascular complications, high-density lipoprotein (HDL)-associated cholesterol confers atheroprotection under obese and/or diabetic conditions. Here we show that hepatocyte-specific deficiency of transcription factor transforming growth factor β 1-stimulated clone (TSC) 22 D1 led to a substantial reduction in HDL levels in both wild-type and obese mice, mediated through the transcriptional down-regulation of the HDL formation pathway in liver. Indeed, overexpression of TSC22D1 promoted high levels of HDL cholesterol in healthy animals, and hepatic expression of TSC22D1 was found to be aberrantly regulated in disease models of opposing energy availability. The hepatic TSC22D1 transcription factor complex may thus represent an attractive target in HDL raising strategies in obesity/diabetes-related dyslipidemia and atheroprotection.
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Jäger
authors.affiliation: Junior Group Cellular Senescence, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Greiner
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Strzoda
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Oksana
authors.initials: O
authors.lastname: Seibert
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Niopek
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Tjeerd P
authors.initials: TP
authors.lastname: Sijmonsma
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Allan
authors.initials: A
authors.lastname: Jones
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Roldan
authors.initials: R
authors.lastname: De Guia
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Martignoni
authors.affiliation: Department of Vascular Medicine, AMC Amsterdam, 1105AZ Amsterdam, Netherlands.
authors.forename: Geesje M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Mauricio B
authors.initials: MB
authors.lastname: Diaz
authors.affiliation: Junior Group Cellular Senescence, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hofmann
authors.affiliation: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, Network Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH) and University Hospital, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
keywords: High density lipoprotein; Lipid metabolism; Liver; Obesity; Transcription