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 vivoTC
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.