Paul Michael Yen

Professor

Email

Contact: 65167332

Bio Research Publications
Dr. Yen currently is 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 previously served as 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 is the recipient of the 2020 AOTA Nagataki Fujifilm Prize for his contributions to clinical and basic thyroid research in Asia.  He also has served as College Master of Sheares College, Duke-NUS Medical School since 2010. He also has served as the clinical faculty advisor for the Duke Overseas Volunteer Expedition (DOVE) program in which medical students deliver primary care in neighboring underdeveloped countries since its inception in 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, Citrin deficiency, diabetes and obesity.  His team's research has laid the theoretical and preclinical foundation for the use of liver-selective thyromimetics and vitamin B12/folate for the treatment of NASH.

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.

 

1.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 NR1HLXR-mediated Scd1 transcription and augments lipotoxicity in hepatic cells. Autophagy 2017; 13:169-186.  (IF 16.0)

2. Zhou J, Chong SY, Lim A, Singh BK, Sinha RA, Salmon AB, Yen PM.  Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging. Aging 2017; 9:583-599. (IF 5.7)

3.  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 6.0)

4.  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 8.2)

5. 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 16.0)

6. 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)

7. 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 16.0)

8. 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 22.7)

9.  Singh BK, Tripathi M, Sandireddy R, Tikno K, Zhou J, Yen PM. Decreased autophagy and fuel switching occur in a senescent hepatic cell model system. Aging 2020 Jul 26;12(14):13958-13978 (IF 5.7)

10. Yavarow ZA, Kang HR, Waskowicz LR, Bay BH, Young SP, Yen PM, Koeberl DD. Fenofibrate rapidly decreases hepatic lipid and glycogen storage in neonatal mice with glycogen storage disease type Ia. Hum Mol Genet 2020 Jan 15;29(2):286-294. (IF 6.2)

11. Tripathi M, Yen PM, Singh BK. Protocol to Generate Senescent Cells from the Mouse Hepatic Cell Line AML12 to Study Hepatic Aging.STAR Protoc. 2020 Jul 1;1(2):100064. 

12. Dong J, Viswanathan S, Adami E, Singh BK, Chothani SP, Ng B, Lim WW, Zhou J, Tripathi M, Ko NSJ, Shekeran SG, Tan J, Lim SY, Wang M, Lio PM, Yen PM, Schafer S, Cook SA, Widjaja AA. Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. Nat Commun. 2021 Jan 4;12(1):66. (IF 14.9)

13. Chaves C, Bruinstroop E, Refetoff S, Yen PM, Anselmo J. Increased Hepatic Fat Content in Patients with Resistance to Thyroid Hormone Beta.Thyroid. 2021 Jul;31(7):1127-1134. (IF 7.8)

14. Zhou J, Singh BK, Ho JP, Lim A, Bruinstroop E, Ohba K, Sinha RA, Yen PM.  
MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophagy. 2021 Dec;17(12):4043-4061. (IF 16.0)

15. Yau WW, Wong KA, Zhou J, Thimmukonda NK, Wu Y, Bay BH, Singh BK, Yen PM. Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue.iScience. 2021 Apr 15;24(5):102434. (IF 5.5)

16. Zhou J, Gauthier K, Ho JP, Lim A, Zhu XG, Han CR, Sinha RA, Cheng SY, Yen  PM. Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle. Endocrinology. 2021 Aug 1;162(8):bqab112. (IF 4.7) 

17. Bruinstroop E, Zhou J, Tripathi M, Yau WW, Boelen A, Singh BK, Yen PM.  
Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression. Mol Metab. 2021 Nov;53:101266. (IF 7.4)

18. Widjaja AA, Dong J, Adami E, Viswanathan S, Ng B, Pakkiri LS, Chothani SP, Singh BK, Lim WW, Zhou J, Shekeran SG, Tan J, Lim SY, Goh J, Wang M, Holgate R, Hearn A, Felkin LE, Yen PM, Dear JW, Drum CL, Schafer S, Cook SA. Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury. Sci Transl Med. 2021 Jun 9;13(597):eaba8146. (IF 18.0)

19. Rajak S, Xie S, Tewari A, Raza S, Wu Y, Bay BH, Yen PM, Sinha RA. MTORC1 inhibition drives crinophagic degradation of glucagon. Mol Metab. 2021 Nov;53:101286. (IF 7.4)

20. Tripathi M, Singh BK, Liehn EA, Lim SY, Tikno K, Castano-Mayan D, Rattanasopa C, Nilcham P, Abdul Ghani SAB, Wu Z, Azhar SH, Zhou J, Hernández-Resèndiz S, Crespo-Avilan GE, Sinha RA, Farah BL, Moe KT, De Silva DA, Angeli V, Singh MK, Singaraja RR, Hausenloy DJ, Yen PM. Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy. Autophagy. 2022 Jan 11:1-11. (IF 16.0)

21. Zhou J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Camat MD, James A, Wu Y, Ching J, Kovalik JP, Lim KH, Cook SA, Bay BH, Singh BK, Yen PM. Thyroid Hormone Decreases Hepatic Steatosis, Inflammation, and Fibrosis in a Dietary Mouse Model of Nonalcoholic Steatohepatitis. Thyroid. 2022 Jun;32(6):725-738. (IF 7.8)

22. Tripathi M, Singh BK, Zhou J, Tikno K, Widjaja A, Sandireddy R, Ghani SABA, George GBB, K Wong K, Pei HJ, Shekeran SG, Sinha RA, Singh MK, Cook SA, Suzuki A,  Lim TR, Cheah C-C, Wang J, Xiao R-P Zhang X, Chow PKH, Yen PM. Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing Syntaxin 17 homocysteinylation. J Hepatol. 2022 Nov;77(5):1246-1255 (IF 30.1)

23. Zhou J, Pang J, Tripathi M, Ho JP, Widjaja A, Shekeran SG, Cook SA, Suzuki A, Diehl AM Petretto E, Singh BK, Yen PM. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents NASH progression. Nature Comm Nat Commun. 2022 Sep 3;13(1):5202  (IF 17.7)