Paul Michael Yen

Professor

Email

Contact: 65167332

Dr. Yen is currently a Professor at Duke-NUS Graduate Medical School in Singapore and Head of the Laboratory of Hormonal Regulation in the Cardiovascular and Metabolic Disorders Program. He also is Professor of Medicine at Duke University School of Medicine, Durham, NC and a member of the Duke Molecular Physiology Institute. He obtained his M.D. from Johns Hopkins, completed residency in internal medicine at University of Chicago, and fellowship training in endocrinology at NIH. He was formerly Assistant Professor at Harvard Medical School, Chief of the Neuro-endocrinology and Molecular Regulation Section of the Clinical Endocrinology Branch at NIDDK (National Institutes of Health, Bethesda, MD), and Associate Professor of Medicine and Pharmacology at Johns Hopkins University School of Medicine. He has served on the editorial boards of Endocrinology, Molecular Endocrinology, and Thyroid. He also is a U.S. board-certified physician in internal medicine as well as endocrinology and metabolism. He is an Asia-Oceanic Thyroid Association (AOTA) Council Member, the AOTA delegate to the World Thyroid Foundation, and the Singapore Representative to the International Iodine Global Network. He also has served as College Master of Sheares College, Duke-NUS Medical School since 2010. His research interests include endocrine regulation of transcription, autophagy, and lipid metabolism in normal and disease states such as non-alcoholic fatty liver disease, GSD1a, diabetes and obesity.

My laboratory uses molecular biological and genomic approaches to study hormonal regulation of transcription, particularly thyroid hormone (TH). We study whether epigenetic changes such as DNA methylation and histone modifications play a role in positive and negative regulation of transcription, endocrine tumors, long-term suppression of negative feedback by TH, and hormone-responsiveness during aging. Recently, we have shown that TH regulates Fox01 via SIRT deacetylation to regulate gluconeogenic genes, and we currently are studying this novel regulatory mechanism in greater detail. We also examine the potential beneficial effects and mechanisms of TH on non-alcoholic fatty liver disease (NAFLD), a common complication of obesity and diabetes.

My laboratory’s recent discovery that TH as well as other hormones and compounds such as caffeine and epigallocatechin-3-gallate (EGCG) can induce autophagy coupled with increased b-oxidation of fatty acid has suggested novel potential therapeutic strategies for this condition. I also have initiated a clinical study examining whether levothyroxine can ameliorate hepatosteatosis and glucose control in diabetic Asian patients in patients with NAFLD. I have collaborated with Dr. Dwight Koeberl, Duke University for the past two years to examine the role of autophagy in the hepatosteatosis and hepatic glycogen storage in G6Pase deficiency. We have found that there is defective autophagy, impaired beta oxidation of fatty acids, and mitochondrial injury and dysfunction in G6Pase deficiency suggesting that correction of the autophagy defect can improve the major hepatic metabolic dysfunctions in this disease.

Selected Publication  

1. Sinha RA, You SH, Zhou J, Siddique MM, Bay BH, Zhu X, Privalsky ML, Cheng SY, Stevens RD, Summers SA, Newgard CB, Lazar MA, Yen PM. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 2012 122:2428-38. (IF 12.8)

2. 
Singh BK, Sinha RA, Zhou J, Xie SY, You SH, Gauthier K, Yen PM. FoxO1-deacetylation regulates thyroid hormone induced transcription of key hepatic gluconeogenic genes. J Biol Chem 2013; 288:30365-72.  (IF 4.6)

3. 
Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y, Ilkayeva OR, Gooding J, Ching J, Zhou J, Martinez L, Xie S, Bay BH, Summers SA, Newgard CB, Yen PM. Caffeine stimulates hepatic lipid metabolism via autophagy-lysosomal pathway. Hepatology 2014 59:1366-80. (IF 13.2)

4. Sinha RA, Singh BK, Zhou J, Wu Y, Farah BL, Ohba,K, Lesmana R, Gooding J, Bay BH, Yen PM

Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling. Autophagy 2015 11:1341-57. (IF 11.4)

5. Singh BK, Sinha RA, Zhou J, Tripathi M, Ohba K, Wang ME, Astapova I, Ghosh S, Hollenberg AN, Gauthier K, Yen PM. Hepatic FOXO1 target genes are co-regulated by thyroid hormone via RICTOR deacetylation and MTORC2-AKT inhibition. J Biol Chem 2016; 291:198-214. (IF 4.6)

6. Farah BL, Landau DJ, Sinha RA, Brooks ED, Wu Y, Fung SY, Tanaka T, Hirayama M, Bay BH, Koeberl DD, Yen PM. Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. J Hepatol 2016; 64:370-9. (IF 12.5)

7. Lesmana R, Singh BK, Sinha RA, Zhou J, Tripathi M, Ohba K, Yajun Wu Y, Yau WY, Bay BH, Yen, PM. Thyroid hormone stimulation of autophagy is essential for mitochondrial biogenesis and activity in skeletal muscle. Endocrinology 2016; 157:23-38 (cover article). (IF 4.6)

8. Tripathi M, Zhang CW, Singh1, Rohit Anthony Sinha BK, Thu MK, DeSilva DA, Yen PM. Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation. Cell Death and Disease. 2016; 7:e2513 (IF 5.66)

9. Sinha RA, Singh BK, Zhou J, Farah BL, Lesmana R, Ohba K, Tripathi M, Ghosh, S, Hollenberg AN, Yen PM. Loss of ULK1 increases RPS6KB1-NCOR1 repression of NR1H/LXR-mediated Scd1 transcription and augments lipotoxicity in hepatic cells. Autophagy 2017; 13:169-186.  (IF 11.4)

10. Zhou J, Chong SY, Lim A, Singh BK, Sinha RA, Salmon AB, Yen PMChanges in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging. Aging 2017; 9:583-599. (IF 4.9)

11. Bruinstroop E, Dalan R, Yang C, Bee YM, Chandran K, Cho LW, Soh SB, Teo EK, Toh SA, Leow MKS, Sinha RA, Sadananthan SA, Michael N, Stapleton H, Leung C, Angus PW, Patel SK, Burrell LM, Chi LS, Fang SC, Velan SS, Yen PM. Low Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients with Type 2 Diabetes Mellitus and NAFLD. J Clin Endocrinol Metab.  2018; 103:2698-2706 (IF 5.5)

12. Singh BK, Sinha RA, Tripathi M, Mendoza A, Ohba K, Zhou J, Ho JP, Chang C-Y, Wu Y, Giguère V, Bay B-H, Vanacker J-M, Ghosh S, Gauthier K, Hollenberg AN, McDonnell DP, Yen PM. Thyroid hormone and estrogen related receptor alpha co-ordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Science Sig 2018 Jun 26;11(536). pii: eaam5855 (IF 6.5)

13. Yau WW, Singh BK, Lesmana R , Zhou J, Sinha RA, Wong KA, Wu Y, Bay B-H, Sugii S, Sun L, Yen PM. Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and mTOR-mediated mitophagy. Autophagy. 2019 Jan;15(1):131-150 (IF 11.4)

14. Zhou J, Waskowicz LR, Lim A, Liao XH, Lian B, Masamune H, Refetoff S, Tran B, Koeberl DD, 
Yen PM. A Liver-Specific Thyromimetic, VK2809, Decreases Hepatosteatosis I GlycogenStorage Disease Type Ia. Thyroid. 2019; 29:1158-1167.(IF 7.8)

15. Siong Tan HW, Anjum B, Shen HM, Ghosh S, Yen PM, Sinha RA. Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels. Autophagy. 2019;15(1455-1459. (IF 11.4)

16. Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D'Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, Tripathi M, Lim SY, Shekeran SG, Chothani SP, Rabes A, Sombetzki M, Bruinstroop E, Min LP, Sinha RA, Albani S, Yen PM, Schafer S, Cook SA. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis. Gastroenterology. 2019;157:777-792. (IF 19.2)


Reviews

1. Sinha RA, Singh BK, Yen PM. Reciprocal Crosstalk Between Autophagic and Endocrine Signaling in Metabolic Homeostasis. Endocr Rev. 2017; 38:69-102 (IF 18.6) 

2. Sinha RA, Singh BK, Yen PM. Direct effects of thyroid hormones on hepatic lipid metabolism.  Nature Rev Endocrin 2018; 4:259-269 (IF 18.3)


3. Sinha RA, Bruinstroop E, Singh BK, Yen PM. Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists. Thyroid. 2019; 29: 1173-1191 ((IF 7.9)