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Cell Metab. 2011 Apr 6;13(4):389-400. doi: 10.1016/j.cmet.2011.02.011.

Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia.

Author information

1
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.
2
Division of Tumor Virology, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
3
Core Facility Tumor Models, German Cancer Research Center Heidelberg, 69120 Heidelberg, Germany.
4
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
5
Medical Research Center, Klinikum Mannheim, 68167 Mannheim, Germany.
6
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.
7
Department of General, Visceral, and Transplantation Surgery, Charité-Universitätsmedizin, Campus Virchow, Free University of Berlin, 13353 Berlin, Germany.
8
Department of Animal Physiology, Philipps University Marburg, 35043 Marburg, Germany.
9
Department of Vascular Medicine, AMC Amsterdam, 1105AZ Amsterdam, Netherlands.
10
Department of Medicine I and Clinical Chemistry, University of Heidelberg, 69120 Heidelberg, Germany.
11
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.

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.

PMID:
21459324
DOI:
10.1016/j.cmet.2011.02.011
[Indexed for MEDLINE]
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