paul m. yen, m.d. laboratory of hormonal regulation cardiovascular and metabolic diseases program...
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Paul M. Yen, M.D.Laboratory of Hormonal RegulationCardiovascular and Metabolic Diseases ProgramDuke-NUS Graduate Medical [email protected]
Thyroid hormone and lipid metabolism: New answers to old questions
10th AOTA CongressOctober 22, 2012
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Metabolic Syndrome
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Obesity: A Recent Metamorphosis During Evolution
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Obesity Trends Among U.S. Adults1988
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% 10%–14
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Obesity Trends Among U.S. Adults 2008
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% 10%–14 15%–19% 20%–24% 25%–29% ≥30%
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Obesity: An Epidemic in Asia
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Prevalence of obesity by NCEP ATP III definition (BMI> 30) and the Asian adapted definition (BMI >25)
Population Prevalence by ATP III Prevalence by Asian
Japan M: 16.8% F:22.3% M: 21.6 F: 31.3%South Korea M: 16%; F: 10.7% M: 29%; F: 16% China All: 10.1% All: 26.3% Singapore M: 13.1%; F: 11% M: 20.9%; F: 15.5% Taiwan M: 11.2%; F: 18.6% M: 23.8%; F: 17.7% Hong Kong M: 15.3%; F: 18.8% M: 20.2%; F: 23.6% Philippines M: 14.3%; F: 14.1% M: 18.6%; F: 19.9%
Asia Pac J Clin Nutr 16:362-367 (2007)
Doi Stroke 40:1187-1194 (2009)
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What role could TH have in metabolic syndrome?
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Metabolic effects of thyroid hormone
• Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.
•Decreases serum cholesterol and triglycerides.
•Stimulates fatty acid mobilization and beta oxidation.
•Increases insulin-mediated glucose uptake, glycogenolysis, and gluconeogenesis.
•Potentiates sympathetic effects on heart and vascular system.
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Metabolic effects of thyroid hormone
• Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.
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d-thyroxine as a treatment for hypercholesterolemia
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TriiodothyronineTiratricol Triiododothyroacetic acid (TRIAC)
FDA recall Still available on internet
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Ingredients: L-Tyrosine, Bovine Thyroid Powder,Bovine Adrenal Powder, Guglipid, Nori, Piper Longum Extract,Ginger Extract
Ingredients:
Thyroid Tissue, Adrenal Tissue, Pituitary Tissue, Thymus Tissue, Spleen Tissue, Kelp.
Ingredients include:
Kelp extractIodine supplement
Herbal Supplements
Thyroid Extracts
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Metabolic effects of thyroid hormone
• Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.
•Decreases serum cholesterol and triglycerides.
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Serum lipids in hypothyroidism
• Hypothyroidism is the most common cause of secondary hyperlipidemia
• Increased serum cholesterol and triglycerides
• Increased LDL>VLDL>HDL; HDL can be increased, unchanged, or decreased; LDL/HDL ratio is increased
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How does thyroid hormone improve dyslipidemia?
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How does thyroid hormone improve dyslipidemia?
• Increased LDLr expression reduces cholesterol due to increased LDL clearance
• Increased LDLr expression reduces TG due to increased LDL and VLDL clearance
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How does thyroid hormone improve dyslipidemia?
• Increased LDLr expression reduces cholesterol due to increased LDL clearance
• Increased LDLr expression reduces TG due to increased LDL and VLDL clearance
• Inhibition of SREBP1 leads to decreased hepatic fatty acid synthesis and VLDL secretion
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How does thyroid hormone improve dyslipidemia?
• Increased LDLr expression reduces cholesterol due to increased LDL clearance
• Increased LDLr expression reduces TG due to increased LDL and VLDL clearance
• Inhibition of SREBP1 leads to decreased hepatic fatty acid synthesis and VLDL secretion
• Increased reverse cholesterol transport. Increased HDL receptor (SRBP1), cholesterol 7α-hydroxylase (CYP7A1), and ABCG.
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Sites of TH action in lipid metabolism
Liberopoulos and Elisaf, Hormones 2002
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Sites of TH action in lipid metabolism
Liberopoulos and Elisaf, Hormones 2002
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Sites of TH action in lipid metabolism
Liberopoulos and Elisaf, Hormones 2002
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Thyroid hormone analogs: Magic bullets for hypercholesterolemia?
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Strategies for TH Analogs
Potential therapies for hypercholesterolemia and obesity
1) Tissue-specific uptake
2) Tissue-specific metabolism and activation (e.g., liver)
3) TR isoform-specific binding
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Thyroid hormone receptor isoforms
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Effects of KB-141 on Serum Cholesterol, Heart Rate, Body weight, and serum Lp(a)
level
Grover et al. PNAS 2003
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GC-1 Effects on Reverse Cholesterol Pathway and Bile Clearance
Johanssen et al. PNAS 2005
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Cholesterol Lowering Effects of GC-1
Grey, control
Green, GC-1 Blue, atorvastatin (Lipitor)
Baxter et al. TEMS 2005
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Effects of Eprotirome (KB2115) on serum levels of cholesterol, lipoproteins, and triglycerides
N Engl J Med 2010;362:906-16
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Changes in serum LDL cholesterol concentration and body weight in patients treated with DITPA
Ladenson P W et al. JCEM 2010;95:1349-1354
DITPA (solid lines) and placebo (dashed)
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Change in cardiac index from baseline over 24 weeks of treatment
Goldman S et al. Circulation 2009;119:3093-3100
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Summary
Isoform-specific and tissue-specific TH analogs may be novel and useful therapiesfor obesity, hyperlipidemia, and hyperglycemia of metabolic syndrome.
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Metabolic effects of thyroid hormone
• Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.
•Decreases serum cholesterol and triglycerides.
•Stimulates fatty acid mobilization and beta oxidation.
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Non-alcoholic fatty liver disease (NAFLD), is a common feature of metabolic syndrome and a silent world-wide epidemic.
NAFLD is a spectrum of disorders characterized by fat accumulation and injury in the liver.
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NAFLD Incidence
• Estimated to occur in 30% American adult population
• Occurs in 60-80% patients with obesity and/or diabetes
• NASH with liver injury occurs in 2-5% of cases
• Occurs in 2.5% of pediatric population
• Rate is increasing worldwide
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NAFLD is a spectrum of liver disorders
Types
1) Fat accumulation in the liver (Steatosis)
2) Fat accumulation and inflammation (Non-alchololic hepatosteatosis (NASH))
3) NASH and fibrosis (Scar tissue in liver)
4) Cirrhosis
5) Hepatocellular carcinoma
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Non-Alcoholic Fatty Liver Disease(NAFLD)
Fatty liver (Steatosis)
Steatohepatitis - inflammation - fibrosis
Cirrhosis
Normal liver
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Liver Damage
Sat FA
2nd Hit
Apoptosis
Hepatocyte Mass and Fibrosis
Fatty Liver
Mechanism for NAFLD
Oxidative stressToxinsInflammatory moleculesInfection
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Thyroid hormone and hepatic lipid catabolism
• Hepatic lipid catabolism involves:1. uptake of free fatty acids (FFA) from circulation and storage2. release of FFA from intra-hepatic lipid droplet stores3. shuttling of free fats into mitochondria followed by β-oxidation
• Thyroid hormone (T3) is known to increase hepatic lipid catabolism by increasing free fatty acid uptake from adipose tissue and mitochondrial shuttling through Cpt1α.
• However little is known about the T3 effects on lipid droplet turnover.
• Hypothyroidism is linked to increase incidence of fatty liver disease characterized by lipid droplet deposition in liver. Pagadala MR et al., Dig Dis Sci. 2012 57:528-34
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Mechanisms of hepatic lipid droplet turnover
Singh R et al. Nature 458:1131-5 (2009)
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Can T3 stimulate autophagy?
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Model of autophagy
www.cellsignal.com
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T3 responsiveness in TR-expressing human hepatocytes (HepG2 cells)
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LC3-B Pepck Cpt1αFold
cha
nge
in e
xpre
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2hrs
control
(+) T3
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*
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T3 induces autophagy in HepG2 cells
(LC3II Western blotting and immunostaining)
DAPI / LC3-II Punctation
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Thyroid hormone (T3) promotes autophagosome and lysosome formation in hepatoma cells
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LC3-II/Bodipy staining shows increased induction of “lipophagy” by T3
Con
trol
T3 t
reat
ed
DAPI/LC3-II BODIPY 493/503
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TH structural analog GC-1 induces autophagy in TR-expressing HepG2 cells
Actin
LC3-II
LC3-I
T3C GC1
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T3 induces hepatic autophagy in vivo and is TR-dependent
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T3 induces hepatic “lipophagy”in vivo
Control T3-treated
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Autophagy mediates T3-induced hepatic β-oxidation in vivo
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Major findings in liver metabolomics: Increased acylcarnitines after T3 treatment and
decreased b-oxidation in NDAD mice
Middle-chain hepatic acylcarnitines are affected by different TH status (hypo vs. hyper)
Long-chain hepatic acylcarnitines are affected by both TH status and NCoR DAD mutation
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Dio1 Dio2 Dio3
MCT8
OATP1B
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SRC-1DO
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NCD
MCD
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Dio1 Dio2 Dio3 MCT8OATP1B3 THRβ NCoR SMRT SRC-1 DOR TRα1 RXRα
NCD 1 1 1 1 1 1 1 1 1 1 1 1
MCD 0.445 3.41 0.51 0.5 0.35 0.57 0.5 0.62 0.58 0.49 0.64 0.88
*p<0.05, Each bar represents the mean of the respective individual ratios ± SEM from unpaired t-test, (n = 4 rats from each group).
T3 signaling may be impaired in fatty liver condition *
* * ** * *
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T3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells
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T3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells
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Summary
1. T3 induces autophagy in cultured hepatocytes and liver in vivo.
2. T3 effects on autophagy and b-oxidation of fatty acids facilitates their clearance and consumption leading to decreased hepatosteatosis
3. T3-mediated autophagy protects hepatocytes from apoptosis induced by fatty acids.
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Conclusions
TH or TH analogs may be useful therapies for obesity, hypercholesterolemia, and NAFLD in patients with metabolic syndrome.
Drugs that promote hepatic autophagy may be useful treatments for NAFLD.
In certain disorders, some tissues may have intracellular deficiency of TH, and tissue-specific or isoform-specific analogs may be potential therapies in these conditions (e.g., liver, heart, brain). Serum TSH only measures pituitary response to TH.
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Collaborators
Laboratory of Hormonal Regulation CVMD
Rohit SinhaChui Sun Yap
Sherwin Xie
Zhou Jin
Brijesh SinhaBenjamin FarahDarius AuAlvin Tan
Lab of Ceramides and Metabolic Disorders CVMD
Scott SummersMonawarul SiddiqueBenjamin Bikman
Dept Anatomy NUS
Bay Boon Huat
Stedman Center, Duke University
Christopher Newgard
Endocrinology and Metabolism Division, Duke
Marc Feinglos
Brittany Bohinc
Diabetes Center, University of Pennsylvania
Mitchell Lazar
Seo-Hee You
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Thanks !!!
Yen Lab
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Thank you!