Hepatic Deficiency in Transcriptional Cofactor TBL1 Promotes Liver Steatosis and Hypertriglyceridemia

• Published in: Cell metabolism 2011-04, Vol.13 (4), p.389-400
• Main Authors: Kulozik, Philipp, Jones, Allan, Mattijssen, Frits, Rose, Adam J., Reimann, Anja, Strzoda, Daniela, Kleinsorg, Stefan, Raupp, Christina, Kleinschmidt, Jürgen, Müller-Decker, Karin, Wahli, Walter, Sticht, Carsten, Gretz, Norbert, von Loeffelholz, Christian, Stockmann, Martin, Pfeiffer, Andreas, Stöhr, Sigrid, Dallinga-Thie, Geesje M., Nawroth, Peter P., Diaz, Mauricio Berriel, Herzig, Stephan
• Format: Article
• Language: English
• Subjects: Animals; Dietary Fats - pharmacology; Dimerization; Disease Models, Animal; Fatty Liver - etiology; Humans; Hypertriglyceridemia - etiology; Lipid Metabolism - physiology; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Nuclear Proteins - metabolism; PPAR alpha - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Repressor Proteins - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Transducin - antagonists & inhibitors; Transducin - genetics; Transducin - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2011.02.011

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. ▴ Hepatic expression of transcriptional cofactor TBL1 is impaired in fatty livers ▴ Hepatic deficiency in TBL1 promotes liver steatosis and hypertriglyceridemia ▴ Hepatic TBL1 acts in concert with TBLR1 and nuclear receptor PPARα