促甲状腺激素（TSH）对肝脏酰基辅酶A：胆固醇酰基转移酶2表达的影响及机制

The abnormality of thyroid hormone (TH) has been widely considered as the underlying mechanism for dyslipidemia in thyroid dysfunction. However, in certain diseases, such as subclinical hypothyroidism (SCH), in which TH levels are maintained at normal levels and only the TSH level is increased, evident elevations in an atherogenic lipid profile and ischemic heart disease are often observed in clinic. Apparently, dyslipidemia in SCH does not result solely from TH deficiency. TSH may play a direct regulatory role on lipid metabolism which has not been explored to date. Acyl-CoA cholesterol acyl transferase (ACAT) is an important enzyme in the formation of cholesteryl esters (CE) from cholesterol. Hepatocytic ACAT2 is a key cholesterol esterification enzyme necessary for the development of hypercholesterolemia. Moreover, CE in the liquid phase comprises a major fraction of the lipid-rich core of the plaque, and its abundance has been associated with plaque rupture and formation of atherothrombosis. No studies have evaluated whether there is a direct effect of TSH on the formation of cholesteryl esters. Our previous research has shown that thyrotropin receptor (TSHR) is present and functional in hepatocytes. Our preliminary study even demonstrated that TSH has a novel role in the promotion of ACAT2 expression that resulted in increased CE level. And the expression of ACAT2 reduced sharply in the TSHR knock-out mice. In the following study, we will explore the effect and mechanism of TSH on the expression of hepatocytic ACAT2. A series of in vivo and in vitro experiments will be performed to ensure the integrity of our theory. The results of our study may be a useful strategy for prevention and treatment of dyslipidemia and atherosclerosis.

传统观点认为甲状腺功能紊乱时血脂异常是甲状腺激素（TH）造成的，但亚临床甲状腺功能减退时，促甲状腺素(TSH)升高，TH正常，依然可以出现血脂紊乱，易于发生动脉粥样硬化，是冠心病的独立危险因素。我们推测升高的TSH在血脂紊乱和动脉粥样硬化的发生中起重要作用。研究显示：细胞内游离胆固醇在酰基辅酶A：胆固醇脂酰转移酶（ACAT）的催化下，生成胆固醇酯，肝脏胆固醇酯的分泌率与冠状动脉粥样硬化的发生呈显著正相关。TSH在胆固醇酯化中是否发挥作用，国内外尚未有研究。我们的前期研究证实肝脏存在有生物活性的TSH受体，TSH可促进肝细胞ACAT2 的表达, 增加胆固醇酯的生成。在TSH受体敲除的小鼠中ACAT2表达明显减少。本研究拟通过体内（甲状腺摘除甲减大鼠模型、TSH受体敲除小鼠、TSH受体RNA干扰小鼠）与体外细胞水平探讨TSH在肝脏对ACAT2表达的影响及机制，揭示TSH致血脂紊乱的新作用。

本项目证实TSH可通过调节肝脏ACAT2的表达进而影响胆固醇的酯化，最终引起血脂紊乱及动脉粥样硬化的发生，研究结果提示TSH在胆固醇代谢中发挥着重要的作用，TSH对胆固醇酯化过程的影响，尤其是揭示了TSH对在此过程中发挥着重要作用的ACAT2的影响及分子机制，进一步揭示了血脂紊乱的分子机制，打破人们对甲状腺功能紊乱致动脉粥样硬化发生机制的传统认识，进一步完善甲状腺疾病患者血脂代谢紊乱进而引发心血管疾病的分子机制，对防治动脉粥样硬化、降低冠心病的患病率和病死率有着重要的意义。.在本项目的资助下还取得了以下成果：证实TSH通过PI3K/Akt/SREBP2/HNF4α通路下调肝脏CYP7A1的表达及活性，抑制肝脏胆固醇转化成胆汁酸，增加肝脏胆固醇含量，为治疗和预防高胆固醇血症提供理论依据。.证实TSH通过cAMP/PKA通路，增强SREBP1c活性，进而促进肝脏生脂基因的表达及活性，增加甘油三酯的合成，促进肝脏脂肪变，为NAFLD提供新的干预靶点。.应用病例-对照研究发现：高甘油三酯血症患者亚甲减的患病风险增加约1.5 倍（OR：男1.507，95%CI 1.265 - 1.794；女1.417; 95% CI, 1.290 -1.556），而且，随着血清甘油三酯浓度的升高，TSH 水平逐渐增加，二者呈显著正相关。研究结果提示脂毒性可能是TSH 水平升高的独立危险因素，为亚甲减早期防治提供新思路。.发现了SLC12A3基因上的两个复合杂合突变，是导致Gitelman综合征发病的原因，并在国际上首次报道。通过基因诊断、随访观察及文献综述为Gitelman综合征的诊断及治疗提供科学依据和新的思路。.本项目共发表文章15篇，全部被SCI收录，总影响因子约70。参加国内国际学术会议4次，口头报告或者壁报交流研究成果。获山东省科技进步奖一等奖一项。培养研究生5名。