Download presentation
1
REGULATION OF CHOLESTEROL METABOLISM BY TSH
JIAJUN ZHAO Department of Endocrinology and Metabolism, Provincial Hospital affiliated to Shandong University Institute of Endocrinology, Shandong Academy of Clinical Medicine
2
knowledge on TSH Background
TSH (thyrotropin,thyroid stimulating hormone): A kind of glycoprotein from adenohypophysis Usually think, thyroid is the only effector of TSH TSH is released by the anterior pituitary gland and is the main regulator of thyroid gland growth and development.
3
TSH receptors locating the thyrocyte membranes
Background knowledge on TSH TSH receptors locating the thyrocyte membranes
4
Distribution of TSHR on extrathyroidal tissues
Intraorbital tissue TSHR mRNA and TSH binding site are found in orbital fibroblasts and preadipocyte,which may relate with thyroid associated ophthalmopathy Adipose tissue First 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 adipocyte Immune System TSHR 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 system TSHR Bone tissue and bone cells TSH plays a role in the process of bone remodeling, bone formation and resorption through binding with TSHR expressed in osteoblasts, osteoclast precursors Others kidney、testis、cardiac muscle、red cell、nerve cell、etc。 Paschke R, J Mol Med Endo TJ Biol Chem. 1995 Mengistu M, J Endocrinol Invest. 1994 Balzan S, Biomed Pharmacother. 2007 Abe E, Cell. 2003 Crisanti P, Endocrinology. 2001
5
Secondary hypercholesterolemia
Background Secondary hypercholesterolemia Hypercholesterolemia: leading to atherosclerosis and increase cardiovascular event risk hypothyroidism: a very important reason for secondary hypercholesterolemia Iervasi, G., et al. Arch Intern Med, (14):
6
Overt hypothyroidism TSH ↑ thyroid hormones normal Cholesterol ↑
Thyroid hormone deficiency contributing to Hypercholesterolemia in hypothyroidism Overt hypothyroidism subclinical hypothyroidism thyroid hormones ↓ TSH ↑ thyroid hormones normal Traditional theory 1.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 ↑
7
X Overt hypothyroidism thyroid hormones TSH ↑ normal ↓ Cholesterol ↑
Thyroid hormone deficiency contributing to Hypercholesterolemia in hypothyroidism Overt hypothyroidism subclinical hypothyroidism thyroid hormones normal thyroid hormones ↓ TSH ↑ Traditional theory It can not be explained by the traditional theory X 1.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 deficiency contributing to Hypercholesterolemia in hypothyroidism Overt hypothyroidis subclinical hypothyroidism thyroid hormones normal thyroid hormones ↓ TSH ↑ Traditional theory 1.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 。 ? X Cholesterol ↑
9
An association of a high TSH level with the elevation of cholesterol
GayJ.Canaris et al. ARCH INTERN MED 2000; VOL160
10
Follow-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 clinic OR euthyroid subclinical hypothyroidism 3.5 3 2.5 2 1.5 1 0.5 Myocardial infarction atherosclerosis 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, : 1734–1740 10
11
The high TSH level is associated with the increased cholesterol levels
Asvold BO’ Study Cholesterol (mmol/L) Asvold BO, et al. Eur J Endocrinol
12
3709 subjects for preliminary data analysis
A cross-sectional study in euthyroid Chinese subjects : Investigating the relationship between serum TSH levels and lipid profiles 4848 subjects for a routine health check-up in Shandong Provincial Hospital in China 1139 subjects were excluded: with abnormal thyroid function taking thyroid medications with chronic liver or renal diseases with any diseases or taking any medicine that might affect thyroid status and lipid metabolism pregnant women 3709 subjects for preliminary data analysis 45 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 evaluation ZHAO JJ et al JCEM 2012
13
0.0598 TSH TC The action of TSH on TC levels consisting of
both direct effects and indirect effects via thyroid hormones 0.3595 gender TT3 FT3 age 0.1422 0.3061 0.0598 TSH 0.1196 FPG TC 0.0873 0.1127 TC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; 0.1041 BMI 0.3974 TT4 FT4 Smoking status . PATH ANALYSIS (Values represent path coefficients)
14
Logistic regression model
A significant linear trend toward higher logTC (P=0.021) levels with increasing serum TSH levels within the reference range Logistic 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)
15
coefficient Categories of age (yr)
The association between TSH and logTC: stronger among the olders than the youngers 0.15 0.1 coefficient 0.05 in the older than the younger 12-29 30-39 40-49 50-59 60-69 70-93 Categories of age (yr) Partial correlations of TSH with log transformation of TC according to categories of age
16
A retrospective study in Shandong Province in China: Euthyroid non-smokers with newly diagnosed asymptomatic coronary heart disease A total of 921 subjects with newly diagnosed asymptomatic CHD subjects 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 women the remaining 521 nonsmokers Dysfunction of thyroid . 406 euthyroid subjects (187 males, 219 females
17
Correlation analysis of thyroid function and serum lipid parameters in euthyroidic patients
Positive and linear association between TSH level and logTC value
18
Effects of TSH on serum lipid levels
Total effects Direct effects Log TC 0.1936 0.2028 Log TG 0.1095 0.1138 Log LDL-C 0.0808 0.0896 Log HDL-C Suggestions: TSH per se play the action effect on cholesterol independent of thyroid hormones in CHD
19
following serum TSH level elevation
Increase in the prevalence rate of hypertriglyceridemia following serum TSH level elevation in the patients with coronary heart disease Even 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 revealed ZHAO JJ et al. Nutr Metab (Lond). 2012
20
suggestions: observation
Therapy issues highlighted in the areas of subclinical hypothyroidism in clinic: yes or not ? Guide to subclinical hypothyroidism therapy if TSH < 10 μIU/mL suggestions: 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 !
21
the treatment strategy on
Therapy issues highlighted in the areas of subclinical hypothyroidism in clinic: yes or not ? Lacking: Direct convincing evidence Between TSH and cholesterol TSH elevation Question ? Influence the treatment strategy on subclinical hypothyroidism Cholesterol increased Increase In atherosclerosis
22
Effect of TSH on liver ? TSH ? Liver Thyroid cholesterol
23
Liver is the most important organ for cholesterol metabolism
24
balance maintaining cholesterol metabolism homeostasis
cholesterol Synthesis balance Cholesterol 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,
25
The fact is really exists: Presence of TSHR in hepatocytes
Confirmation: mRNA and proteins of TSHR Zhao JJ et al J Cell Mol Med ,2009
26
The fact is really exists : TSHR in hepatocytes
TSHR proteins locating on the membrane of hepatocytes .
27
TSHR is functional TSH AC a: L-02 cells; b: CHO(negative control) c: human primary normal cells; d:NBL mouse cells C: control;FOR: AC agonist; GLU: glocugan TSH binding with the TSHR plays its biological role mainly through adenylyl cyclase (AC) pathway to increased intracellular cAMP accumulation
28
HMG-COA reductase a rate-limiting enzyme in cholesterol synthetize
Liver is the major organ for cholesterol synthesis HMG-CoA reductase(HMGCR) is the rate-limited enzyme in cholesterol synthesis the liver expresses HMGCR with the highest abundance
29
Confirm the TSH effects in Rat hypothyroidism model
Experimental Design In 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.
30
TSH increases HMGCR mRNA, protein and activity
31
Cholesterol contents were increased by TSH in vivo
TC S M L TSH T4
32
Mechanism of the increased cholesterol contents by TSH in hepatocytes
TSH directly up-regulates hepatic HMGCR activity resulting in elevated serum TC via TSHR/cAMP/pCREB signaling pathway ZHAO,JJ et al HEPATOLOGY 2010
33
Imbalance ??? ??? maintaining cholesterol metabolism homeostasis
cholesterol inicrease by TSH Imbalance ??? cholesterol conversion to bile acids ???
34
TSH decreases cholesterol conversion
Decrease in CYP7A1 proten (green) Decrease in Bile acid contents
35
The contents of bile acids are increased in TSHR-KO mice
Wild type TSHR-KO mice (T4 supplement) Elevated CYP7A1 activity Increased bile acid contents
36
Conclusions TSH can affect cholesterol metabolism including synthesis and conversion in liver The TSH level, even within the normal range, is positively and linearly correlated with serum total cholesterol level TSH increases the cholesterol level driving from TSH up-regulating HMGCR activity leading to an increase in cholesterol synthesis TSH down-regulating the CYP7A1 activity resulting in a decrease in cholesterol conversion, both contributing together to the cholesterol elevation.
Similar presentations
© 2025 SlidePlayer.com. Inc.
All rights reserved.