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

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% %–14

5. Obesity Trends Among U.S. Adults 2008
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% %– %–19% %–24% %–29% ≥30%

6. Obesity: An Epidemic in Asia

7. South Korea M: 16%; F: 10.7% M: 29%; F: 16%
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: (2009)
Asia Pac J Clin Nutr 16: (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 Ingredients include: Supplements Kelp extract Iodine supplement
Thyroid Extracts
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.

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. 1) Tissue-specific uptake
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
Changes (±95% confidence intervals) in serum LDL cholesterol concentration (A) and body weight (B) in patients treated with DITPA (solid lines) and placebo (dashed lines) for 24 wk.
DITPA (solid lines) and placebo (dashed)
Ladenson P W et al. JCEM 2010;95:

31. Change in cardiac index from baseline over
24 weeks of treatment
Figure 2. Change in cardiac index from baseline (with 90% CIs) over 24 weeks of treatment; also shown is average DITPA dose over time in those patients. n, DITPA and n, Placebo refer to the number of patients actually receiving each treatment at that time point.
Goldman S et al. Circulation 2009;119:

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
NAFLD Incidence

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
NAFLD is a spectrum of liver disorders

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

38. Mechanism for NAFLD 2nd Hit Sat FA Apoptosis Fatty Liver Liver Damage
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 :528-34

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

41. Can T3 stimulate autophagy?

42. Model of autophagy

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
LC3-II
LC3-I T3 C
GC1

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

51. 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

52. T3 signaling may be impaired in fatty liver condition* * * * * * * *
Dio1
Dio2
Dio3
MCT8
OATP1B3
THRβ
NCoR
SMRT
SRC-1
DOR
TRα1
RXRα
NCD 1
MCD
0.445
3.41
0.51
0.5
0.35
0.57
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).

53. T3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells

54. T3 blocks apoptosis and induces autophagy
due to lipotoxicity in HepG2 cells

55. Summary
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.

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 Rohit Sinha Laboratory of Hormonal Regulation CVMD
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. Thanks !!!
Yen Lab

59. Thank you!