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10 th AOTA Congress October 22, 2012

10 th AOTA Congress October 22, 2012. 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. Metabolic Syndrome.

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10 th AOTA Congress October 22, 2012

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  1. 10th AOTA CongressOctober 22, 2012 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

  2. Metabolic Syndrome

  3. Obesity: A Recent Metamorphosis During Evolution

  4. Obesity Trends Among U.S. Adults1988 (*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 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% Doi Stroke 40:1187-1194 (2009) Asia Pac J Clin Nutr 16:362-367 (2007)

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

  13. Herbal Supplements Ingredients include: Kelp extract Iodine supplement Thyroid Extracts Ingredients:  L-Tyrosine, Bovine Thyroid Powder,Bovine Adrenal Powder, Guglipid, Nori, Piper Longum Extract,Ginger Extract

  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. 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

  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 AnalogsPotential 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 DITPA (solid lines) and placebo (dashed) Ladenson P W et al. JCEM 2010;95:1349-1354

  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 injury in 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 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

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

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

  39. Thyroid hormone and hepatic lipid catabolism • Hepatic lipid catabolism involves: • uptake of free fatty acids (FFA) from circulation and storage • release of FFA from intra-hepatic lipid droplet stores • 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

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

  41. Can T3 stimulate autophagy?

  42. Model of autophagy www.cellsignal.com

  43. * * * T3 responsiveness in TR-expressing human hepatocytes (HepG2 cells)

  44. T3 induces autophagy in HepG2 cells (LC3II Western blotting and immunostaining) DAPI / LC3-II Punctation

  45. Thyroid hormone (T3) promotes autophagosome and lysosome formation in hepatoma cells

  46. LC3-II/Bodipy staining shows increased induction of “lipophagy” by T3 DAPI/LC3-II BODIPY 493/503 Control T3 treated

  47. TH structural analog GC-1 induces autophagy in TR-expressing HepG2 cells Actin C T3 GC1 LC3-I LC3-II

  48. T3 induces hepatic autophagy in vivo and is TR-dependent

  49. T3 induces hepatic “lipophagy”in vivo Control T3-treated

  50. Autophagy mediates T3-induced hepatic β-oxidation in vivo

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