Presentation on theme: "10th AOTA Congress October 22, 2012"— Presentation transcript:
110th AOTA Congress October 22, 2012 Thyroid hormone and lipid metabolism: New answers to old questionsPaul M. Yen, M.D.Laboratory of Hormonal RegulationCardiovascular and Metabolic Diseases ProgramDuke-NUS Graduate Medical School
9Metabolic 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.
10Metabolic effects of thyroid hormone Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.
11d-thyroxine as a treatment for hypercholesterolemia
12Still available on internet FDA recallTiratricolTriiododothyroacetic acid (TRIAC)Triiodothyronine
14Metabolic effects of thyroid hormone Increases metabolic rate, O2 consumption, ATP hydrolysis leading to heat production and weight loss.Decreases serum cholesterol and triglycerides.
15Serum lipids in hypothyroidism Hypothyroidism is the most common cause of secondary hyperlipidemiaIncreased serum cholesterol and triglyceridesIncreased LDL>VLDL>HDL; HDL can be increased, unchanged, or decreased; LDL/HDL ratio is increased
17How does thyroid hormone improve dyslipidemia? Increased LDLr expression reduces cholesterol due to increased LDL clearanceIncreased LDLr expression reduces TG due to increased LDL and VLDL clearance
18How does thyroid hormone improve dyslipidemia? Increased LDLr expression reduces cholesterol due to increased LDL clearanceIncreased LDLr expression reduces TG due to increased LDL and VLDL clearanceInhibition of SREBP1 leads to decreased hepatic fatty acid synthesis and VLDL secretion
19How does thyroid hormone improve dyslipidemia? Increased LDLr expression reduces cholesterol due to increased LDL clearanceIncreased LDLr expression reduces TG due to increased LDL and VLDL clearanceInhibition of SREBP1 leads to decreased hepatic fatty acid synthesis and VLDL secretionIncreased reverse cholesterol transport. Increased HDL receptor (SRBP1), cholesterol 7α-hydroxylase (CYP7A1), and ABCG.
20Sites of TH action in lipid metabolism Liberopoulos and Elisaf, Hormones 2002
21Sites of TH action in lipid metabolism Liberopoulos and Elisaf, Hormones 2002
22Sites of TH action in lipid metabolism Liberopoulos and Elisaf, Hormones 2002
23Thyroid hormone analogs: Magic bullets for hypercholesterolemia?
241) Tissue-specific uptake Strategies for TH Analogs Potential therapies for hypercholesterolemia and obesity1) Tissue-specific uptake2) Tissue-specific metabolism and activation (e.g., liver)3) TR isoform-specific binding
26Effects of KB-141 on Serum Cholesterol, Heart Rate, Body weight, and serum Lp(a) level Grover et al. PNAS 2003
27GC-1 Effects on Reverse Cholesterol Pathway and Bile Clearance Johanssen et al. PNAS 2005
28Cholesterol Lowering Effects of GC-1 Grey, controlGreen, GC-1Blue, atorvastatin (Lipitor)Baxter et al. TEMS 2005
29Effects of Eprotirome (KB2115) on serum levels of cholesterol, lipoproteins, and triglyceridesN Engl J Med 2010;362:906-16
30Changes 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:
31Change in cardiac index from baseline over 24 weeks of treatmentFigure 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:
32Summary Isoform-specific and tissue-specific TH analogs may be novel and useful therapiesfor obesity, hyperlipidemia, and hyperglycemiaof metabolic syndrome.
33Metabolic 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.
34Non-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.
35NAFLD Incidence Estimated to occur in 30% American adult population Occurs in 60-80% patients with obesity and/or diabetesNASH with liver injury occurs in 2-5% of casesOccurs in 2.5% of pediatric populationRate is increasing worldwideNAFLD Incidence
36NAFLD 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 carcinomaNAFLD is a spectrum of liver disorders
38Mechanism for NAFLD 2nd Hit Sat FA Apoptosis Fatty Liver Liver Damage Oxidative stressToxinsInflammatory moleculesInfection2nd HitSat FALiver DamageApoptosisHepatocyte Mass and Fibrosis
39Thyroid hormone and hepatic lipid catabolism Hepatic lipid catabolism involves:uptake of free fatty acids (FFA) from circulation and storagerelease of FFA from intra-hepatic lipid droplet storesshuttling of free fats into mitochondria followed by β-oxidationThyroid 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
40Mechanisms of hepatic lipid droplet turnover Singh R et al. Nature 458: (2009)
43T3 responsiveness in TR-expressing human hepatocytes (HepG2 cells) *
44T3 induces autophagy in HepG2 cells (LC3II Western blotting and immunostaining) DAPI / LC3-II Punctation
45Thyroid hormone (T3) promotes autophagosome and lysosome formation in hepatoma cells
46LC3-II/Bodipy staining shows increased induction of “lipophagy” by T3 DAPI/LC3-IIBODIPY 493/503ControlT3 treated
47TH structural analog GC-1 induces autophagy in TR-expressing HepG2 cells ActinLC3-IILC3-IT3CGC1
48T3 induces hepatic autophagy in vivo and is TR-dependent
49T3 induces hepatic “lipophagy”in vivo ControlT3-treated
50Autophagy mediates T3-induced hepatic β-oxidation in vivo
51Major findings in liver metabolomics: Increased acylcarnitines after T3 treatment and decreased b-oxidation in NDAD miceMiddle-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
52T3 signaling may be impaired in fatty liver condition ********Dio1Dio2Dio3MCT8OATP1B3THRβNCoRSMRTSRC-1DORTRα1RXRαNCD1MCD0.4453.410.510.50.350.570.620.580.490.640.88*p<0.05, Each bar represents the mean of the respective individual ratios ± SEM from unpaired t-test, (n = 4 rats from each group).
53T3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells
54T3 blocks apoptosis and induces autophagy due to lipotoxicity in HepG2 cells
55SummaryT3 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 hepatosteatosis3. T3-mediated autophagy protects hepatocytes from apoptosis induced by fatty acids.
56ConclusionsTH 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.
57Collaborators Rohit Sinha Laboratory of Hormonal Regulation CVMD Chui Sun YapSherwin XieZhou JinBrijesh SinhaBenjamin FarahDarius AuAlvin TanLab of Ceramides and Metabolic Disorders CVMDScott SummersMonawarul SiddiqueBenjamin BikmanDept 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