Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia

Cell Metab. 2011 Apr 6;13(4):389-400. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Repressor Proteins / metabolism
  • Transducin / antagonists & inhibitors
  • Transducin / genetics
  • Transducin / metabolism*


  • Dietary Fats
  • Nuclear Proteins
  • PPAR alpha
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • TBL1XR1 protein, human
  • Tbl1x protein, mouse
  • Transducin