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REGULATION OF CHOLESTEROL METABOLISM BY TSH JIAJUN ZHAO Department of Endocrinology and Metabolism, Provincial Hospital affiliated to Shandong University.

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Presentation on theme: "REGULATION OF CHOLESTEROL METABOLISM BY TSH JIAJUN ZHAO Department of Endocrinology and Metabolism, Provincial Hospital affiliated to Shandong University."— Presentation transcript:

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  TSH (thyrotropin , thyroid stimulating hormone): A kind of glycoprotein from adenohypophysis  Usually think, thyroid is the only effector of TSH Background

3 TSH receptors locating the thyrocyte membranes knowledge on TSH Background

4 Distribution of TSHR on extrathyroidal tissues TSHR 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 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 Mengistu M, J Endocrinol Invest Balzan S, Biomed Pharmacother Abe E, Cell Crisanti P, Endocrinology. 2001

5 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): Background

6 Overt hypothyroidism subclinical hypothyroidism TSH ↑ thyroid hormones ↓ thyroid hormones normal Cholesterol ↑ Traditional theory Thyroid hormone deficiency contributing to Hypercholesterolemia in hypothyroidism

7 Overt hypothyroidism subclinical hypothyroidism TSH ↑ thyroid hormones ↓ thyroid hormones normal Cholesterol ↑ Traditional theory It can not be explained by the traditional theory X Thyroid hormone deficiency contributing to Hypercholesterolemia in hypothyroidism

8 Overt hypothyroidis subclinical hypothyroidism TSH ↑ thyroid hormones ↓ thyroid hormones normal Cholesterol ↑ Traditional theory ? X Thyroid hormone deficiency contributing to Hypercholesterolemia in hypothyroidism

9 GayJ.Canaris et al. ARCH INTERN MED 2000; VOL160 An association of a high TSH level with the elevation of cholesterol

10 OR OR OR OR euthyroid subclinical hypothyroidism subclinical hypothyroidism atherosclerosis Myocardialinfarction Follow-up study of Whickham ’ study ( 20 years ) S Razvi, et al. J Clin Endocrinol Metab, : 1734–1740 Even mildly elevated TSH : Testing the elevated serum total cholesterol and an increase in atherosclerosis and cardiovascular event risk in clinic

11 Asvold BO’ Study Asvold BO, et al. Eur J Endocrinol The high TSH level is associated with the increased cholesterol levels Cholesterol (mmol/L)

12 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 euthyroid subjects for final evaluation A cross-sectional study in euthyroid Chinese subjects : Investigating the relationship between serum TSH levels and lipid profiles ZHAO JJ et al JCEM 2012JCEM

13 gender age BMI TT3FT3 TT4FT TSH TC FPG Smoking status The action of TSH on TC levels consisting of both direct effects and indirect effects via thyroid hormones PATH ANALYSIS ( Values represent path coefficients )

14 Logistic regression model 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) A significant linear trend toward higher logTC (P=0.021) levels with increasing serum TSH levels within the reference range

15 The association between TSH and logTC: stronger among the olders than the youngers Categories of age (yr) coefficient 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 effectsDirect effects Log TC Log TG Log LDL-C Log HDL-C Suggestions: TSH per se play the action effect on cholesterol independent of thyroid hormones in CHD

19 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 Increase in the prevalence rate of hypertriglyceridemia following serum TSH level elevation in the patients with coronary heart disease ZHAO JJ et al. Nutr Metab (Lond). 2012Nutr Metab (Lond).

20 Guide to subclinical hypothyroidism therapy if TSH < 10 μIU/mL suggestions: observation The patients with elevated serum TSH levels (<10 μIU/mL) in subclinical hypothyroidism : up to 75% ! Therapy issues highlighted in the areas of subclinical hypothyroidism in clinic: yes or not ? Most patients do not be received the active timely treatment ! ( Col, N.F., et al JAMA )

21 Cholesterol increased TSH elevation Lacking: Direct convincing evidence Between TSH and cholesterol Question ? Influence the treatment strategy on subclinical hypothyroidism Increase In atherosclerosis Therapy issues highlighted in the areas of subclinical hypothyroidism in clinic: yes or not ?

22 TSH Thyroid ? cholesterol Liver Effect of TSH on liver ?

23 Liver is the most important organ for cholesterol metabolism

24 cholesterol Synthesis Cholesterol Conversion to bile acids balance maintaining cholesterol metabolism homeostasis

25 T he 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 binding with the TSHR plays its biological role mainly through adenylyl cyclase (AC) pathway to increased intracellular cAMP accumulation  a  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 AC

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 Experimental Design Rat sham-operated control(Sh) thyroidectomized (Tx) No T4 injectionT4 injection large dose TSH injection Small dose TSH injection No TSH injection Confirm the TSH effects in Rat hypothyroidism model 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 TSH TC T4 TSH -- S M L Cholesterol contents were increased by TSH in vivo + +

32 Mechanism of the increased cholesterol contents by TSH in hepatocytes ZHAO,JJ et al HEPATOLOGY 2010 TSH directly up-regulates hepatic HMGCR activity resulting in elevated serum TC via TSHR/cAMP/pCREB signaling pathway

33 cholesterol inicrease by TSH cholesterol conversion to bile acids Imbalance maintaining cholesterol metabolism homeostasis ???

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 TSHR-KOWild type Elevated CYP7A1 activityIncreased bile acid contents

36 Conclusions synthesis  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.

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