title: Ligand-dependent corepressor acts as a novel corepressor of thyroid hormone receptor and represses hepatic lipogenesis in mice.
abstract: OBJECTIVE
  Transcriptional co-regulators assist nuclear receptors to control the transcription and maintain the metabolic homeostasis. Ligand-dependent corepressor (LCOR) was reported to function as a transcriptional corepressor in vitro. We found LCOR expression decreased in fatty livers of leptin-deficient (ob/ob) mice, diet-induced obese mice, as well as patients, suggesting LCOR may play a role in lipid homeostasis. We sought to investigate the physiological role of LCOR in vivo and elucidate the underlining molecular mechanisms.
  
  
  METHODS
  The effect of LCOR on hepatic lipid accumulation and thyroid hormone receptor (TR) mediated expression of lipogenic genes was studied in vitro and in vivo.
  
  
  RESULTS
  Ectopic expression of LCOR via intravenous infection with LCOR adenovirus decreased the hepatic triglyceride level in wild type, ob/ob, and diet-induced obese mice. Interestingly, overexpression of LCOR repressed the thyroid hormone induced expression of lipogenic genes and non-lipogenic genes, and ameliorated hepatic steatosis in obese mice, suggesting that LCOR might regulate lipogenesis as a novel TR corepressor. Furthermore, our study revealed that LCOR could interact with TRβ1 in the presence of the ligand, which resulted in competitive binding and reduced recruitment of steroid receptor coactivator-1/3 (SRC-1/3) to the promoter region of TR target genes.
  
  
  CONCLUSIONS
  Our data suggest that LCOR is likely to suppress TRβ1-mediated hepatic lipogenesis by decreasing binding and recruitment of SRCs to TRβ1. Our study reveals the physiological function of hepatic LCOR in lipid metabolism and the mechanism by which LCOR regulates lipogenesis. Hepatic LCOR may be a potential target for treating hepatic steatosis.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Song
authors.forename: Shifang
authors.initials: S
authors.lastname: Shan
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Weiqiao
authors.initials: W
authors.lastname: Ding
authors.forename: Wenxia
authors.initials: W
authors.lastname: Ren
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Xia
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Xihua
authors.initials: X
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
mesh_terms: D000818:Animals; D056970:Co-Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D054730:Protein Interaction Domains and Motifs; D037021:Thyroid Hormone Receptors alpha / Q000737:chemistry / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D008024:Ligands; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta