کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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6102374 | 1211115 | 2014 | 7 صفحه PDF | دانلود رایگان |
Background & AimsHallmarks 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.MethodsAs the function of TSH is mediated through the TSH receptor (TSHR), Tshrâ/â mice (supplemented with thyroxine) were used. Liver steatosis and triglyceride content were analysed in Tshrâ/â and Tshr+/+ mice fed a high-fat or normal chow diet, as well as in Srebp-1câ/â and Tshrâ/âSrebp-1câ/â mice. The expression levels of proteins and genes involved in liver triglyceride metabolism was measured.ResultsCompared with control littermates, the high-fat diet induced a relatively low degree of liver steatosis in Tshrâ/â mice. Even under chow diet, hepatic triglyceride content was decreased in Tshrâ/â 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 Tshrâ/â mice. In Tshrâ/âSrebp-1câ/â mice, the liver triglyceride content showed no significant difference compared with Tshr+/+Srebp-1câ/â 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.ConclusionsTSH increased the hepatic triglyceride content, indicating an essential role for TSH in the pathogenesis of NAFLD.
Journal: Journal of Hepatology - Volume 61, Issue 6, December 2014, Pages 1358-1364