Thyroid hormone-responsive SPOT 14 homolog promotes hepatic lipogenesis, and its expression is regulated by Liver X receptor α through a sterol regulatory element-binding protein 1c-dependent mechanism in mice

Jing Wu, Chunjiong Wang, Shuo Li, Sha Li, Wanyi Wang, Jing Li, Yujing Chi, Hang Yang, Xiaomu Kong, Yunfeng Zhou, Chengyan Dong, Fan Wang, Guoheng Xu, Jichun Yang, Jan Åke Gustafsson, Youfei Guan

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The protein, thyroid hormone-responsive SPOT 14 homolog (Thrsp), has been reported to be a lipogenic gene in cultured hepatocytes, implicating an important role of Thrsp in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Thrsp expression is known to be regulated by a variety of transcription factors, including thyroid hormone receptor, pregnane X receptor, and constitutive androstane receptor. Emerging in vitro evidence also points to a critical role of liver X receptor (LXR) in regulating Thrsp transcription in hepatocytes. In the present study, we showed that Thrsp was up-regulated in livers of db/db mice and high-fat-diet-fed mice, two models of murine NAFLD. Hepatic overexpression of Thrsp increased triglyceride accumulation with enhanced lipogenesis in livers of C57Bl/6 mice, whereas hepatic Thrsp gene silencing attenuated the fatty liver phenotype in db/db mice. LXR activator TO901317 induced Thrsp expression in livers of wild-type (WT) and LXR-β gene-deficient mice, but not in LXR-α or LXR-α/β double-knockout mice. TO901317 treatment significantly enhanced hepatic sterol regulatory element-binding protein 1c (SREBP-1c) expression and activity in WT mice, but failed to induce Thrsp expression in SREBP-1c gene-deficient mice. Sequence analysis revealed four LXR response-element-like elements and one sterol regulatory element (SRE)-binding site within a -2,468 ∼+1-base-pair region of the Thrsp promoter. TO901317 treatment and LXR-α overexpression failed to induce, whereas overexpression of SREBP-1c significantly increased Thrsp promoter activity. Moreover, deletion of the SRE site completely abolished SREBP-1c-induced Thrsp transcription. Conclusion: Thrsp is a lipogenic gene in the liver that is induced by the LXR agonist through an LXR-α-mediated, SREBP-1c-dependent mechanism. Therefore, Thrsp may represent a potential therapeutic target for the treatment of NAFLD.

Original languageEnglish (US)
Pages (from-to)617-628
Number of pages12
JournalHepatology
Volume58
Issue number2
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Hepatology

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