Transcript Regulation of Cholesterol Metabolism by TSH

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]
Background
knowledge on TSH
 TSH (thyrotropin，thyroid stimulating hormone):
A kind of glycoprotein from adenohypophysis
 Usually think, thyroid is the only effector of TSH
Background
knowledge on TSH
TSH receptors locating the thyrocyte membranes
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
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
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, 2007. 167(14): 1526-32.
Thyroid hormone deficiency
contributing to Hypercholesterolemia in hypothyroidism
subclinical hypothyroidism
Overt hypothyroidism
thyroid hormones
↓
TSH ↑
thyroid hormones
normal
Traditional theory
Cholesterol ↑
Thyroid hormone deficiency
contributing to Hypercholesterolemia in hypothyroidism
subclinical hypothyroidism
Overt hypothyroidism
thyroid hormones
↓
TSH ↑
thyroid hormones
normal
It can not be
explained by the
traditional theory
Traditional theory
X
Cholesterol ↑
Thyroid hormone deficiency
contributing to Hypercholesterolemia in hypothyroidism
subclinical hypothyroidism
Overt hypothyroidis
thyroid hormones
↓
Traditional theory
TSH ↑
？
Cholesterol ↑
thyroid hormones
normal
X
An association of a high TSH level with the elevation of cholesterol
GayJ.Canaris et al. ARCH INTERN MED 2000; VOL160
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
3.5
atherosclerosis
Myocardial
infarction
1.1-2.6
1.3-4.0
3
2.5
2
O
R
1.5
1
0.5
0
euthyroid
subclinical
hypothyroidism
S Razvi , et al. J Clin Endocrinol Metab, 2010. 95: 1734–1740
The high TSH level is associated with the increased cholesterol levels
(mmol/L)
Cholesterol
Asvold BO’ Study
Asvold BO, et al. Eur J Endocrinol. 2007.
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
The action of TSH on TC levels consisting of
both direct effects and indirect effects via thyroid hormones
TT3
0.3595
gender
FT3
-0.2652
-0.0298
0.1422
0.0598
TSH
TC
age
0.3061
0.1196
0.0873
0.1127
- 0.2256
TT4
0.3974
PATH
0.1041
FT4
ANALYSIS
.
(Values represent path coefficients)
FPG
Smoking
status
BMI
A significant linear trend toward higher logTC (P=0.021) levels
with increasing serum TSH levels within the reference range
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)
The association between TSH and logTC:
stronger among the olders than the youngers
coefficient
0.15
0.1
0.05
0
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
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
Correlation analysis of thyroid function and serum lipid parameters
in euthyroidic patients
Positive and linear association
between TSH level and logTC value
Effects of TSH on serum lipid levels
Log TC
Log TG
Log LDL-C
Log HDL-C
Suggestions:
Total effects
Direct effects
0.1936
0.1095
0.0808
-0.0391
0.2028
0.1138
0.0896
-0.0446
TSH per se play the action effect on cholesterol
independent of thyroid hormones in CHD
Increase in the prevalence rate of hypertriglyceridemia
following serum TSH level elevation
in the patients with coronary heart disease
25
%
Prevalence of Hypercholesterolaemia
20
15
10
5
0
0.27
0.27-1.58
1.59-2.88
2.89-4.2
>4.2
Serum TSH concentration (mIU/L)
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
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. 2004 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 !
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
Cholesterol
increased
Increase
In
atherosclerosis
Influence
the treatment
strategy on
subclinical
hypothyroidism
Effect of TSH on liver ?
TSH
?
Liver
Thyroid
cholesterol
Liver is the most important organ
for cholesterol metabolism
maintaining cholesterol metabolism homeostasis
cholesterol Synthesis
balance
Cholesterol Conversion to bile acids
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
The fact is really exists : TSHR in hepatocytes
TSHR proteins locating on the membrane of hepatocytes
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
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
Confirm the TSH effects in Rat hypothyroidism model
Experimental Design
Rat
sham-operated
control(Sh)
thyroidectomiz
ed (Tx)
No T4
injection
T4 injection
large dose TSH
injection
Small dose TSH
injection
No TSH
injection
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.
TSH increases HMGCR mRNA, protein and activity
HMGCR activity
(pmol/min•mg
protein)
Activity
30
20
10
0
Activity
0
0.1
1
4
4.8
9.4
16.8
20.5
bTSH (μM)
Cholesterol contents were increased by TSH in vivo
TSH
TC
-+
S
M
L
TSH
+
+
+
T4
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
maintaining cholesterol metabolism homeostasis
cholesterol inicrease by TSH
Imbalance
???
cholesterol conversion to bile acids
???
TSH decreases cholesterol conversion
Decrease in
Bile acid contents
Decrease in CYP7A1 proten
(green)
The contents of bile acids
are increased in TSHR-KO mice
TSHR-KO
Elevated CYP7A1 activity
Wild type
Increased bile acid contents
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.