Fang Yan1, Qi Wang2, Ming Lu1, Wenbin Chen3, Yongfeng Song1, Fei Jing1, Youfei Guan4, Laicheng Wang3, Yanliang Lin3, Tao Bo3, Jie Zhang3, Tingting Wang5, Wei Xin3, Chunxiao Yu1, Qingbo Guan1, Xinli Zhou1, Ling Gao6, Chao Xu7, Jiajun Zhao8. 1. Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China. 2. Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Pharmacology of Shandong University, Jinan, China. 3. Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China. 4. Department of Physiology and Pathophysiology, Shenzhen University Health Science Center, Shenzhen, China. 5. Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China. 6. Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China; Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, China. 7. 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. 8. 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.
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.
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: So Yoon Choi; Dae Yong Yi; Soon Chul Kim; Ben Kang; Byung Ho Choe; Yoon Lee; Yoo Min Lee; Eun Hye Lee; Hyo Jeong Jang; You Jin Choi; Hyun Jin Kim Journal: J Korean Med Sci Date: 2021-05-24 Impact factor: 2.153