Slide 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 jjzhao@memdail.com.cn

Slide 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

Slide 3

TSH receptors locating the thyrocyte membranes knowledge on TSH Background

Slide 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. 1995. Endo TJ Biol Chem. 1995 Mengistu M, J Endocrinol Invest. 1994 Balzan S, Biomed Pharmacother. 2007 Abe E, Cell. 2003 Crisanti P, Endocrinology. 2001

Slide 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, 2007. 167(14): 1526-32. Background

Slide 6

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

Slide 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

Slide 8

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

Slide 9

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

Slide 10

OR OR OR OR euthyroid subclinical hypothyroidism subclinical hypothyroidism 3.5 3 2.5 2 1.5 1 0.5 0 atherosclerosis1.1-2.6 Myocardialinfarction1.3-4.0 Follow-up study of Whickham study ( 20 years S Razvi, et al. J Clin Endocrinol Metab, 2010. 95: 17341740 Even mildly elevated TSH : Testing the elevated serum total cholesterol and an increase in atherosclerosis and cardiovascular event risk in clinic

Slide 11

Asvold BO Study Asvold BO, et al. Eur J Endocrinol. 2007. The high TSH level is associated with the increased cholesterol levels Cholesterol (mmol/L)

Slide 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. 3664 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

Slide 13

- 0.2256 0.0873 0.1196 0.3061 0.1041 0.1422 0.1127 -0.0298 0.3974 -0.2652 gender age BMI TT3FT3 TT4FT4 0.0598 0.3595. 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 )

Slide 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

Slide 15

The association between TSH and logTC: stronger among the olders than the youngers 0 0.05 0.1 0.15 12-2930-3940-4950-5960-6970-93 Categories of age (yr) coefficient Partial correlations of TSH with log transformation of TC according to categories of age

Slide 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

Slide 17

Correlation analysis of thyroid function and serum lipid parameters in euthyroidic patients Positive and linear association between TSH level and logTC value

Slide 18

Effects of TSH on serum lipid levels Total effectsDirect effects Log TC0.19360.2028 Log TG0.10950.1138 Log LDL-C0.08080.0896 Log HDL-C-0.0391-0.0446 Suggestions: TSH per se play the action effect on cholesterol independent of thyroid hormones in CHD

Slide 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).

Slide 20

Guide to subclinical hypothyroidism therapy if TSH < 10 IU/mL suggestions: observation The patients with elevated serum TSH levels (

Slide 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 ?

Slide 22

TSH Thyroid ? cholesterol Liver Effect of TSH on liver ?

Slide 23

Liver is the most important organ for cholesterol metabolism

Slide 24

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

Slide 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

Slide 26

The fact is really exists : TSHR in hepatocytes TSHR proteins locating on the membrane of hepatocytes

Slide 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

Slide 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

Slide 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.

Slide 30

TSH increases HMGCR mRNA, protein and activity

Slide 31

TSH TC T4 TSH -- S M L Cholesterol contents were increased by TSH in vivo + +

Slide 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

Slide 33

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

Slide 34

TSH decreases cholesterol conversion Decrease in CYP7A1 proten (green) Decrease in Bile acid contents

Slide 35

The contents of bile acids are increased in TSHR-KO mice TSHR-KOWild type Elevated CYP7A1 activityIncreased bile acid contents

Slide 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.

Slide 37