Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor

J Clin Invest. 2015 Jan;125(1):183-93. doi: 10.1172/JCI73615. Epub 2014 Dec 1.


Inflammation in response to excess low-density lipoproteins in the blood is an important driver of atherosclerosis development. Due to its ability to enhance ATP-binding cassette A1-dependent (ABCA1-dependent) reverse cholesterol transport (RCT), liver X receptor (LXR) is an attractive target for the treatment of atherosclerosis. However, LXR also upregulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), leading to increased hepatic triglyceride synthesis, an independent risk factor for atherosclerosis. Here, we developed a strategy to separate the favorable and unfavorable effects of LXR by exploiting the specificity of the coactivator thyroid hormone receptor-associated protein 80 (TRAP80). Using human hepatic cell lines, we determined that TRAP80 selectively promotes the transcription of SREBP-1c but not ABCA1. Adenovirus-mediated expression of shTRAP80 inhibited LXR-dependent SREBP-1c expression and RNA polymerase II recruitment to the LXR responsive element (LXRE) of SREBP-1c, but not to the LXRE of ABCA1. In murine models, liver-specific knockdown of TRAP80 ameliorated liver steatosis and hypertriglyceridemia induced by LXR activation and maintained RCT stimulation by the LXR ligand. Together, these data indicate that TRAP80 is a selective regulator of hepatic lipogenesis and is required for LXR-dependent SREBP-1c activation. Moreover, targeting the interaction between TRAP80 and LXR should facilitate the development of potential LXR agonists that effectively prevent atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Cholesterol / metabolism
  • Gene Expression
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lipogenesis*
  • Liver / metabolism*
  • Liver X Receptors
  • Macrophages, Peritoneal / metabolism
  • Male
  • Mediator Complex / physiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Orphan Nuclear Receptors / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Transcriptional Activation


  • Liver X Receptors
  • Med17 protein, human
  • Mediator Complex
  • Orphan Nuclear Receptors
  • Sterol Regulatory Element Binding Protein 1
  • Cholesterol