title: Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia.
abstract: The aberrant accumulation of lipids in the liver ("fatty liver") is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Philipp
authors: P
authors: Kulozik
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Allan
authors: A
authors: Jones
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Frits
authors: F
authors: Mattijssen
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Adam J
authors: AJ
authors: Rose
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Anja
authors: A
authors: Reimann
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Daniela
authors: D
authors: Strzoda
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Kleinsorg
authors: Division of Tumor Virology, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Christina
authors: C
authors: Raupp
authors: Division of Tumor Virology, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Jürgen
authors: J
authors: Kleinschmidt
authors: Core Facility Tumor Models, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Karin
authors: K
authors: Müller-Decker
authors: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors: Walter
authors: W
authors: Wahli
authors: Medical Research Center, Klinikum Mannheim, 68167 Mannheim, Germany.
authors: Carsten
authors: C
authors: Sticht
authors: Medical Research Center, Klinikum Mannheim, 68167 Mannheim, Germany.
authors: Norbert
authors: N
authors: Gretz
authors: Department of Endocrinology, Diabetes, and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany; Department of Clinical Nutrition, German Institute of Nutrition, 14558 Potsdam, Germany.
authors: Christian
authors: C
authors: von Loeffelholz
authors: Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin, Campus Virchow, Free University of Berlin, 13353 Berlin, Germany.
authors: Martin
authors: M
authors: Stockmann
authors: Department of Endocrinology, Diabetes, and Nutrition, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany; Department of Clinical Nutrition, German Institute of Nutrition, 14558 Potsdam, Germany.
authors: Andreas
authors: A
authors: Pfeiffer
authors: Department of Animal Physiology, Philipps University Marburg, 35043 Marburg, Germany.
authors: Sigrid
authors: S
authors: Stöhr
authors: Department of Vascular Medicine, AMC Amsterdam, 1105AZ Amsterdam, Netherlands.
authors: Geesje M
authors: GM
authors: Dallinga-Thie
authors: Department of Medicine I and Clinical Chemistry, University of Heidelberg, 69120 Heidelberg, Germany.
authors: Peter P
authors: PP
authors: Nawroth
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
authors: Mauricio Berriel
authors: MB
authors: Diaz
authors: Joint Division of Molecular Metabolic Control, DKFZ-ZMBH Alliance, Center for Molecular Biology Heidelberg, University Hospital Heidelberg, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany. Electronic address: s.herzig@dkfz.de.
authors: Stephan
authors: S
authors: Herzig
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D019281:Dimerization; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology*; D006801:Humans; D015228:Hypertriglyceridemia / Q000209:etiology*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015293:Transducin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D009687:Nuclear Proteins; D047493:PPAR alpha; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; C485613:Tbl1x protein, mouse; D015293:Transducin