title: Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity.
abstract: OBJECTIVE
  Hallmarks of non-alcoholic fatty liver disease (NAFLD) are increased triglyceride accumulation within hepatocytes. The prevalence of NAFLD increases steadily with increasing thyrotropin (TSH) levels. However, the underlying mechanisms are largely unknown. Here, we focused on exploring the effect and mechanism of TSH on the hepatic triglyceride content.
  
  
  METHODS
  As the function of TSH is mediated through the TSH receptor (TSHR), Tshr(-/-) mice (supplemented with thyroxine) were used. Liver steatosis and triglyceride content were analysed in Tshr(-/-) and Tshr(+/+) mice fed a high-fat or normal chow diet, as well as in Srebp-1c(-/-) and Tshr(-/-)Srebp-1c(-/-) mice. The expression levels of proteins and genes involved in liver triglyceride metabolism was measured.
  
  
  RESULTS
  Compared with control littermates, the high-fat diet induced a relatively low degree of liver steatosis in Tshr(-/-) mice. Even under chow diet, hepatic triglyceride content was decreased in Tshr(-/-) mice. TSH caused concentration- and time-dependent effects on intracellular triglyceride contents in hepatocytes in vitro. The activity of SREBP-1c, a key regulator involved in triglyceride metabolism and in the pathogenesis of NAFLD, was significantly lower in Tshr(-/-) mice. In Tshr(-/-)Srebp-1c(-/-) mice, the liver triglyceride content showed no significant difference compared with Tshr(+/+)Srebp-1c(-/-) mice. When mice were injected with forskolin (cAMP activator), H89 (inhibitor of PKA) or AICAR (AMPK activator), or HeG2 cells received MK886 (PPARα inhibitor), triglyceride contents presented in a manner dependent on SREBP-1c activity. The mechanism, underlying TSH-induced liver triglyceride accumulation, involved that TSH, through its receptor TSHR, triggered hepatic SREBP-1c activity via the cAMP/PKA/PPARα pathway associated with decreased AMPK, which further increased the expression of genes associated with lipogenesis.
  
  
  CONCLUSIONS
  TSH increased the hepatic triglyceride content, indicating an essential role for TSH in the pathogenesis of NAFLD.
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Pharmacology of Shandong University, Jinan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.affiliation: Department of Physiology and Pathophysiology, Shenzhen University Health Science Center, Shenzhen, China.
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Laicheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Bo
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Guan
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China. Electronic address: doctorxuchao@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China. Electronic address: jjzhao@medmail.com.cn.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D047493:PPAR alpha / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013972:Thyrotropin / Q000378:metabolism* / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D047493:PPAR alpha; D011989:Receptors, Thyrotropin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D013972:Thyrotropin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Hepatic steatosis; Peroxisome proliferator-activated receptor α; Sterol regulatory element-binding protein 1c; Thyrotropin (TSH); Triglyceride