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.
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.


CONCLUSIONS
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.
Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Cardiovascular Science of the Ministry of Education, Beijing, China.
Jing
J
Wu
Chunjiong
C
Wang
Shuo
S
Li
Sha
S
Li
Wanyi
W
Wang
Jing
J
Li
Yujing
Y
Chi
Hang
H
Yang
Xiaomu
X
Kong
Yunfeng
Y
Zhou
Chengyan
C
Dong
Fan
F
Wang
Guoheng
G
Xu
Jichun
J
Yang
Jan-Åke
JÅ
Gustafsson
Youfei
Y
Guan
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D065626:Non-alcoholic Fatty Liver Disease; D009687:Nuclear Proteins / Q000502:physiology*; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014157:Transcription Factors; C000605214:Nr1h3 protein, mouse; C497388:Srebf1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C501477:Thrsp protein, mouse