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Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity.
J Hepatol 2014; 61(6):1358-64JH

Abstract

BACKGROUND & AIMS

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+Show Affiliations

Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Pharmacology of Shandong University, Jinan, China.Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Department of Physiology and Pathophysiology, Shenzhen University Health Science Center, Shenzhen, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China.Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25016220

Citation

Yan, Fang, et al. "Thyrotropin Increases Hepatic Triglyceride Content Through Upregulation of SREBP-1c Activity." Journal of Hepatology, vol. 61, no. 6, 2014, pp. 1358-64.
Yan F, Wang Q, Lu M, et al. Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. J Hepatol. 2014;61(6):1358-64.
Yan, F., Wang, Q., Lu, M., Chen, W., Song, Y., Jing, F., ... Zhao, J. (2014). Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. Journal of Hepatology, 61(6), pp. 1358-64. doi:10.1016/j.jhep.2014.06.037.
Yan F, et al. Thyrotropin Increases Hepatic Triglyceride Content Through Upregulation of SREBP-1c Activity. J Hepatol. 2014;61(6):1358-64. PubMed PMID: 25016220.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. AU - Yan,Fang, AU - Wang,Qi, AU - Lu,Ming, AU - Chen,Wenbin, AU - Song,Yongfeng, AU - Jing,Fei, AU - Guan,Youfei, AU - Wang,Laicheng, AU - Lin,Yanliang, AU - Bo,Tao, AU - Zhang,Jie, AU - Wang,Tingting, AU - Xin,Wei, AU - Yu,Chunxiao, AU - Guan,Qingbo, AU - Zhou,Xinli, AU - Gao,Ling, AU - Xu,Chao, AU - Zhao,Jiajun, Y1 - 2014/07/10/ PY - 2014/01/07/received PY - 2014/06/12/revised PY - 2014/06/30/accepted PY - 2014/7/13/entrez PY - 2014/7/13/pubmed PY - 2015/8/26/medline KW - Hepatic steatosis KW - Peroxisome proliferator-activated receptor α KW - Sterol regulatory element-binding protein 1c KW - Thyrotropin (TSH) KW - Triglyceride SP - 1358 EP - 64 JF - Journal of hepatology JO - J. Hepatol. VL - 61 IS - 6 N2 - BACKGROUND & AIMS: 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. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/25016220/Thyrotropin_increases_hepatic_triglyceride_content_through_upregulation_of_SREBP_1c_activity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(14)00468-1 DB - PRIME DP - Unbound Medicine ER -