REGULATION OF CHOLESTEROL METABOLISM BY TSH JIAJUN ZHAO Department of Endocrinology and Metabolism,...
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REGULATION OF CHOLESTEROL METABOLISM BY TSH JIAJUN ZHAO Department of Endocrinology and Metabolism, Provincial Hospital affiliated to Shandong University
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 [email protected]
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knowledge on TSH TSH (thyrotropin thyroid stimulating hormone):
A kind of glycoprotein from adenohypophysis Usually think, thyroid
is the only effector of TSH Background
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TSH receptors locating the thyrocyte membranes knowledge on TSH
Background
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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
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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
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Overt hypothyroidism subclinical hypothyroidism TSH thyroid
hormones thyroid hormones normal Cholesterol Traditional theory
Thyroid hormone deficiency contributing to Hypercholesterolemia in
hypothyroidism
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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
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Overt hypothyroidis subclinical hypothyroidism TSH thyroid
hormones thyroid hormones normal Cholesterol Traditional theory X
Thyroid hormone deficiency contributing to Hypercholesterolemia in
hypothyroidism
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GayJ.Canaris et al. ARCH INTERN MED 2000; VOL160 An association
of a high TSH level with the elevation of cholesterol
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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
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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)
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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
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- 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 )
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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
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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
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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
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Correlation analysis of thyroid function and serum lipid
parameters in euthyroidic patients Positive and linear association
between TSH level and logTC value
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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
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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).
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Guide to subclinical hypothyroidism therapy if TSH < 10
IU/mL suggestions: observation The patients with elevated serum TSH
levels (
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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 ?
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TSH Thyroid ? cholesterol Liver Effect of TSH on liver ?
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Liver is the most important organ for cholesterol
metabolism
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cholesterol Synthesis Cholesterol Conversion to bile acids
balance maintaining cholesterol metabolism homeostasis
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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
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The fact is really exists : TSHR in hepatocytes TSHR proteins
locating on the membrane of hepatocytes
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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
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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
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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.
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TSH increases HMGCR mRNA, protein and activity
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TSH TC T4 TSH -- S M L Cholesterol contents were increased by
TSH in vivo + +
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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
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cholesterol inicrease by TSH cholesterol conversion to bile
acids Imbalance maintaining cholesterol metabolism homeostasis
???
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TSH decreases cholesterol conversion Decrease in CYP7A1 proten
(green) Decrease in Bile acid contents
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The contents of bile acids are increased in TSHR-KO mice
TSHR-KOWild type Elevated CYP7A1 activityIncreased bile acid
contents
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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.