Presentation on theme: "REGULATION OF CHOLESTEROL METABOLISM BY TSH"— Presentation transcript:
1REGULATION OF CHOLESTEROL METABOLISM BY TSH JIAJUN ZHAODepartment of Endocrinology and Metabolism, Provincial Hospital affiliated to Shandong UniversityInstitute of Endocrinology, Shandong Academy of Clinical Medicine
2knowledge on TSH Background TSH (thyrotropin，thyroid stimulating hormone):A kind of glycoprotein from adenohypophysisUsually think, thyroid is the only effector of TSHTSH is released by the anterior pituitary gland and is the main regulator of thyroid gland growth and development.
3TSH receptors locating the thyrocyte membranes Backgroundknowledge on TSHTSH receptors locating the thyrocyte membranes
4Distribution of TSHR on extrathyroidal tissues Intraorbital tissueTSHR mRNA and TSH binding site are found in orbital fibroblasts and preadipocyte，which may relate with thyroid associated ophthalmopathyAdipose tissueFirst to be found，now have found that fountional TSHR could be expressed in human adipocyte and preadipocyte, can regulate the growth、 differentiation and endocrine function of adipocyteImmune SystemTSHR is selected expressed in peripheral immune system cells、bone marrow cell population and Lymph node T cells, and involved in the interaction of the immune-nervous-endocrine systemTSHRBone tissue and bone cellsTSH plays a role in the process of bone remodeling, bone formation and resorption through binding with TSHR expressed in osteoblasts, osteoclast precursorsOtherskidney、testis、cardiac muscle、red cell、nerve cell、etc。Paschke R, J Mol MedEndo TJ Biol Chem. 1995Mengistu M, J Endocrinol Invest. 1994Balzan S, Biomed Pharmacother. 2007Abe E, Cell. 2003Crisanti P, Endocrinology. 2001
5Secondary hypercholesterolemia BackgroundSecondary hypercholesterolemiaHypercholesterolemia:leading to atherosclerosis and increase cardiovascular event riskhypothyroidism:a very important reason for secondary hypercholesterolemiaIervasi, G., et al. Arch Intern Med, (14):
6Overt hypothyroidism TSH ↑ thyroid hormones normal Cholesterol ↑ Thyroid hormone deficiencycontributing to Hypercholesterolemia in hypothyroidismOvert hypothyroidismsubclinical hypothyroidismthyroid hormones ↓TSH ↑thyroid hormonesnormalTraditional theory1.甲状腺功能减退症患者多伴有血胆固醇水平的升高，是动脉粥样硬化的独立危险因素。2. 传统理论：甲状腺功能减退时胆固醇水平的升高是甲状腺激素降低的结果3. 亚临床甲减患者甲状腺激素水平正常，仅TSH升高，其血清胆固醇水平也是升高的，目前尚无合理理论解释2005、2010年我国成人甲减的患病率分别为3.5%、6.5%.甲状腺功能减退症已呈流行趋势 。Cholesterol ↑
7X Overt hypothyroidism thyroid hormones TSH ↑ normal ↓ Cholesterol ↑ Thyroid hormone deficiencycontributing to Hypercholesterolemia in hypothyroidismOvert hypothyroidismsubclinical hypothyroidismthyroid hormonesnormalthyroid hormones↓TSH ↑Traditional theoryIt can not be explained by the traditional theoryX1.甲状腺功能减退症患者多伴有血胆固醇水平的升高，是动脉粥样硬化的独立危险因素。2. 传统理论：甲状腺功能减退时胆固醇水平的升高是甲状腺激素降低的结果3. 亚临床甲减患者甲状腺激素水平正常，仅TSH升高，其血清胆固醇水平也是升高的，目前尚无合理理论解释2005、2010年我国成人甲减的患病率分别为3.5%、6.5%.甲状腺功能减退症已呈流行趋势 。Cholesterol ↑
8？ X Overt hypothyroidis thyroid hormones TSH ↑ normal ↓ Cholesterol ↑ Thyroid hormone deficiencycontributing to Hypercholesterolemia in hypothyroidismOvert hypothyroidissubclinical hypothyroidismthyroid hormonesnormalthyroid hormones↓TSH ↑Traditional theory1.甲状腺功能减退症患者多伴有血胆固醇水平的升高，是动脉粥样硬化的独立危险因素。2. 传统理论：甲状腺功能减退时胆固醇水平的升高是甲状腺激素降低的结果3. 亚临床甲减患者甲状腺激素水平正常，仅TSH升高，其血清胆固醇水平也是升高的，目前尚无合理理论解释2005、2010年我国成人甲减的患病率分别为3.5%、6.5%.甲状腺功能减退症已呈流行趋势 。？XCholesterol ↑
9An association of a high TSH level with the elevation of cholesterol GayJ.Canaris et al. ARCH INTERN MED 2000; VOL160
10Follow-up study of Whickham’ study ( 20 years） Even mildly elevated TSH :Testing the elevated serum total cholesterol and an increase in atherosclerosis and cardiovascular event risk in clinicOReuthyroidsubclinical hypothyroidism3.532.521.510.5Myocardialinfarctionatherosclerosis注：一项横断面研究，共纳入病例30656，通过一般线性模型，评估TSH与血脂（总胆固西醇，甘油三酯，非高密度脂蛋白，高密度脂蛋白）之间的线性关系。S Razvi , et al. J Clin Endocrinol Metab, : 1734–174010
11The high TSH level is associated with the increased cholesterol levels Asvold BO’ StudyCholesterol(mmol/L)Asvold BO, et al. Eur J Endocrinol
123709 subjects for preliminary data analysis A cross-sectional study in euthyroid Chinese subjects :Investigating the relationship between serum TSH levels and lipid profiles4848 subjects for a routine health check-up in Shandong Provincial Hospital in China1139 subjects were excluded:with abnormal thyroid functiontaking thyroid medicationswith chronic liver or renal diseaseswith any diseases or taking any medicine that might affect thyroid status and lipid metabolismpregnant women3709 subjects for preliminary data analysis45 subjects whose absolute value of residual standard deviation is less than 3 with regression analysis of two variables by one factor.3664 euthyroid subjects for final evaluationZHAO JJ et al JCEM 2012
130.0598 TSH TC The action of TSH on TC levels consisting of both direct effects and indirect effects via thyroid hormones0.3595genderTT3FT3age0.14220.30610.0598TSH0.1196FPGTC0.08730.1127TC及其影响因素路径图. TSH对TC的作用: 来自其本身的直接作用和通过甲状腺激素的间接作用;0.1041BMI0.3974TT4FT4Smokingstatus.PATH ANALYSIS(Values represent path coefficients)
14Logistic regression model A significant linear trend toward higher logTC (P=0.021) levelswith increasing serum TSH levels within the reference rangeLogistic regression model正常甲状腺功能按 TSH 分层，六个组的高胆固醇血症的患病率绘成折线图A significantlineartrendtowardhigherlogTC(P0.021)and logtriglyceride (P0.001) levelswithincreasingserumTSHlevelswithinthereferencerange Compared with subjects in the lower part o the reference range(TSH level, 0.27–0.61 mIU/liter), the adjusted odds ratio for hypercholesterolemia was (95% confidence interval,1.392–7.538;P=0.007) for those in the upper category (TSH level, 4.61–5.5mIU/liter).随着TSH的增加，高胆固醇血症的患病率有增高的趋势，尚无统计学意义（p = 0.322）。Compared with subjects in the lower part o the reference range (TSH level, 0.27–0.61 mIU/liter), the hypercholesterolemia risk is high in the upper category (TSH level, 4.61–5.5mIU/liter)
15coefficient Categories of age (yr) The association between TSH and logTC:stronger among the olders than the youngers0.150.1coefficient0.05in the older than the younger12-2930-3940-4950-5960-6970-93Categories of age (yr)Partial correlations of TSH with log transformation of TC according to categories of age
16A retrospective study in Shandong Province in China: Euthyroid non-smokers with newly diagnosed asymptomatic coronary heart diseaseA total of 921 subjects with newly diagnosed asymptomatic CHDsubjects were excluded:Without information on vital status or with missing data on serum TSH or thyroxine levels (n=66)Taking medications that might affect FT4 or TSH levels or lipid profiles (n=68)Having neurologic diseases,hepatic disorders, renal disorders, or euthyroid sick syndrome (abnormal low serum FT3 but normal FT4 and TSH) (n=98)smokers including both present and past to baccousers (n=168)pregnant womenthe remaining 521 nonsmokersDysfunction of thyroid .406 euthyroid subjects (187 males, 219 females
17Correlation analysis of thyroid function and serum lipid parameters in euthyroidic patients Positive and linear associationbetween TSH level and logTC value
18Effects of TSH on serum lipid levels Total effectsDirect effectsLog TC0.19360.2028Log TG0.10950.1138Log LDL-C0.08080.0896Log HDL-CSuggestions:TSH per se play the action effect on cholesterolindependent of thyroid hormones in CHD
19following serum TSH level elevation Increase in the prevalence rate of hypertriglyceridemiafollowing serum TSH level elevationin the patients with coronary heart diseaseEven after adjusting for confounding factors, such as sex,age,smoking status, fasting plasma glucos elevels and thyroid hormones, a significant positive impact of TSH on the serum total cholesterol level is also revealedZHAO JJ et al. Nutr Metab (Lond). 2012
20suggestions: observation Therapy issues highlighted in the areas of subclinical hypothyroidism in clinic: yes or not ?Guide to subclinical hypothyroidism therapyif TSH < 10 μIU/mLsuggestions: observation（ Col, N.F., et al JAMA）The patients with elevated serum TSH levels (<10 μIU/mL)in subclinical hypothyroidism : up to 75% ！Most patients do not be received the active timely treatment !
21the treatment strategy on Therapy issues highlighted in the areas of subclinical hypothyroidism in clinic: yes or not ?Lacking:Direct convincing evidenceBetween TSH and cholesterolTSH elevationQuestion?Influencethe treatment strategy onsubclinical hypothyroidismCholesterol increasedIncreaseInatherosclerosis
22Effect of TSH on liver ?TSH?LiverThyroidcholesterol
23Liver is the most important organ for cholesterol metabolism
24balance maintaining cholesterol metabolism homeostasis cholesterol SynthesisbalanceCholesterol Conversion to bile acids简单滴说，及通过这2 方面维持胆固醇平衡， 前面谈到的TSH 增加胆固醇，
25The fact is really exists: Presence of TSHR in hepatocytes Confirmation: mRNA and proteins of TSHRZhao JJ et al J Cell Mol Med ,2009
26The fact is really exists : TSHR in hepatocytes TSHR proteins locating on the membrane of hepatocytes.
27TSHR is functionalTSHACa: L-02 cells；b: CHO（negative control）c: human primary normal cells；d：NBL mouse cellsC: control；FOR: AC agonist； GLU: glocuganTSH binding with the TSHR plays its biological role mainlythrough adenylyl cyclase (AC) pathway to increased intracellular cAMP accumulation
28HMG-COA reductase a rate-limiting enzyme in cholesterol synthetize Liver is the major organ for cholesterol synthesisHMG-CoA reductase(HMGCR) is the rate-limited enzyme in cholesterol synthesisthe liver expresses HMGCR with the highest abundance
29Confirm the TSH effects in Rat hypothyroidism model Experimental DesignIn order to exclude the effect of negative feedback, artificial control the endogenous TSH level, we establish hypothyroidism model through surgical removal of the rat thyroid gland.
31Cholesterol contents were increased by TSH in vivo TCS M LTSHT4
32Mechanism of the increased cholesterol contents by TSH in hepatocytes TSH directly up-regulates hepatic HMGCR activity resulting in elevated serum TCvia TSHR/cAMP/pCREB signaling pathwayZHAO,JJ et al HEPATOLOGY 2010
33Imbalance ??? ??? maintaining cholesterol metabolism homeostasis cholesterol inicrease by TSHImbalance???cholesterol conversion to bile acids???
35The contents of bile acids are increased in TSHR-KO mice Wild typeTSHR-KO mice (T4 supplement)Elevated CYP7A1 activityIncreased bile acid contents
36ConclusionsTSH can affect cholesterol metabolism including synthesis and conversion in liverThe TSH level, even within the normal range, is positively and linearly correlated with serum total cholesterol levelTSH increases the cholesterol level driving from TSH up-regulating HMGCR activity leading to an increase in cholesterol synthesisTSH down-regulating the CYP7A1 activity resulting in a decrease in cholesterol conversion, both contributing together to the cholesterol elevation.