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Paul M. Yen, M.D. Laboratory of Hormonal Regulation Cardiovascular and Metabolic Diseases Program Duke-NUS Graduate Medical School

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Presentation on theme: "Paul M. Yen, M.D. Laboratory of Hormonal Regulation Cardiovascular and Metabolic Diseases Program Duke-NUS Graduate Medical School"— Presentation transcript:

1 Paul M. Yen, M.D. Laboratory of Hormonal Regulation Cardiovascular and Metabolic Diseases Program Duke-NUS Graduate Medical School paul.yen@duke-nus.edu.sg Thyroid hormone and lipid metabolism: New answers to old questions 10 th AOTA Congress October 22, 2012

2 Metabolic Syndrome

3 Obesity: A Recent Metamorphosis During Evolution

4 Obesity Trends Among U.S. Adults 1988 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%–14

5 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%

6 Obesity: An Epidemic in Asia

7 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 JapanM: 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)

8 What role could TH have in metabolic syndrome?

9 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.

10 Metabolic effects of thyroid hormone Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.

11 d-thyroxine as a treatment for hypercholesterolemia

12 Triiodothyronine Tiratricol Triiododothyroacetic acid (TRIAC) FDA recall Still available on internet

13 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 extract Iodine supplement Herbal Supplements Thyroid Extracts

14 Metabolic effects of thyroid hormone Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss. Decreases serum cholesterol and triglycerides.

15 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

16 How does thyroid hormone improve dyslipidemia?

17 Increased LDLr expression reduces cholesterol due to increased LDL clearance Increased LDLr expression reduces TG due to increased LDL and VLDL clearance

18 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

19 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.

20 Sites of TH action in lipid metabolism Liberopoulos and Elisaf, Hormones 2002

21 Sites of TH action in lipid metabolism Liberopoulos and Elisaf, Hormones 2002

22 Sites of TH action in lipid metabolism Liberopoulos and Elisaf, Hormones 2002

23 Thyroid hormone analogs: Magic bullets for hypercholesterolemia?

24 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

25 Thyroid hormone receptor isoforms

26 Effects of KB-141 on Serum Cholesterol, Heart Rate, Body weight, and serum Lp(a) level Grover et al. PNAS 2003

27 GC-1 Effects on Reverse Cholesterol Pathway and Bile Clearance Johanssen et al. PNAS 2005

28 Cholesterol Lowering Effects of GC-1 Grey, control Green, GC-1 Blue, atorvastatin (Lipitor) Baxter et al. TEMS 2005

29 Effects of Eprotirome (KB2115) on serum levels of cholesterol, lipoproteins, and triglycerides N Engl J Med 2010;362:906-16

30 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)

31 Change in cardiac index from baseline over 24 weeks of treatment Goldman S et al. Circulation 2009;119:3093-3100

32 Summary Isoform-specific and tissue-specific TH analogs may be novel and useful therapies for obesity, hyperlipidemia, and hyperglycemia of metabolic syndrome.

33 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.

34 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 injuryin the liver.

35 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

36 NAFLD is a spectrum of liver disorders Types1) Fat accumulation in the liver (Steatosis)2) Fat accumulation and inflammation (Non- alchololic hepatosteatosis (NASH)) 3) NASH and fibrosis (Scar tissue in liver)4) Cirrhosis5) Hepatocellular carcinoma

37 Non-Alcoholic Fatty Liver Disease (NAFLD) Fatty liver (Steatosis) Steatohepatitis - inflammation - inflammation - fibrosis - fibrosis Cirrhosis Normal liver

38 Liver Damage Sat FA 2 nd Hit Apoptosis Hepatocyte Mass and Fibrosis Fatty Liver Mechanism for NAFLD Oxidative stress Toxins Inflammatory molecules Infection

39 Thyroid hormone and hepatic lipid catabolism Hepatic lipid catabolism involves: 1. uptake of free fatty acids (FFA) from circulation and storage 2. release of FFA from intra-hepatic lipid droplet stores 3. shuttling of free fats into mitochondria followed by β-oxidation Thyroid hormone (T 3 ) 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 T 3 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

40 Mechanisms of hepatic lipid droplet turnover Singh R et al. Nature 458:1131-5 (2009)

41 Can T 3 stimulate autophagy?

42 Model of autophagy www.cellsignal.com

43 T 3 responsiveness in TR-expressing human hepatocytes (HepG2 cells) * * *

44 T 3 induces autophagy in HepG2 cells (LC3II Western blotting and immunostaining) DAPI / LC3-II Punctation

45 Thyroid hormone (T 3 ) promotes autophagosome and lysosome formation in hepatoma cells

46 LC3-II/Bodipy staining shows increased induction of lipophagy by T 3 Control T 3 treated DAPI/LC3-IIBODIPY 493/503

47 TH structural analog GC-1 induces autophagy in TR-expressing HepG2 cells Actin LC3-II LC3-I T3T3 CGC1

48 T 3 induces hepatic autophagy in vivo and is TR-dependent

49 T 3 induces hepatic lipophagyin vivo ControlT 3- treated

50 Autophagy mediates T 3 -induced hepatic β-oxidation in vivo

51 Major findings in liver metabolomics: Increased acylcarnitines after T 3 treatment and decreased -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

52 ** ** ** Dio1Dio2Dio3MCT8 OATP1 B3THRβNCoRSMRTSRC-1DORTRα1RXRα NCD111111111111 MCD0.4453.410.510.50.350.570.50.620.580.490.640.88 *p<0.05, Each bar represents the mean of the respective individual ratios ± SEM from unpaired t-test, (n = 4 rats from each group). T 3 signaling may be impaired in fatty liver condition * * * ****

53 T 3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells

54 T 3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells

55 Summary 1.T 3 induces autophagy in cultured hepatocytes and liver in vivo. 2. T 3 effects on autophagy and -oxidation of fatty acids facilitates their clearance and consumption leading to decreased hepatosteatosis 3. T 3 -mediated autophagy protects hepatocytes from apoptosis induced by fatty acids.

56 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.

57 Collaborators Laboratory of Hormonal Regulation CVMD Rohit Sinha Chui Sun Yap Sherwin Xie Zhou Jin Brijesh Sinha Benjamin Farah Darius Au Alvin Tan Lab of Ceramides and Metabolic Disorders CVMD Scott Summers Monawarul Siddique Benjamin 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

58 Yen Lab

59 Thank you!


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