title: Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor.
abstract: 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.
authors.forename: Geun Hyang
authors.initials: GH
authors.lastname: Kim
authors.forename: Gyun-Sik
authors.initials: GS
authors.lastname: Oh
authors.forename: Jin
authors.initials: J
authors.lastname: Yoon
authors.forename: Gang Gu
authors.initials: GG
authors.lastname: Lee
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: Seung-Whan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D056892:Mediator Complex / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000071518:Liver X Receptors; C538713:Med17 protein, human; D056892:Mediator Complex; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D002784:Cholesterol