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Brijesh Kumar Singh

Assistant Professor

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Bio Research Publications

I have done my masters degree in Biotechnology in the year 2004 and awarded Council of Scientific & Industrial Research (CSIR) - India, national fellowship to pursue doctoral research. I joined Indian Institute of Toxicology Research (CSIR) in the year 2005 as CSIR - junior research fellow, where later I promoted to senior research fellow. I did my Ph.D. in the area of Drug induced mitochondrial dysfunction during hepatotoxicity, and finished it in May’ 2011. Afterward, I joined Prof. Paul M Yen (Associate Professor, Program in Cardiovascular & Metabolic Disorders, Duke-NUS Graduate Medical School Singapore) in Oct’ 2011 as post-Doctoral research Fellow. With him, I am investigating the molecular mechanisms modulating nuclear hormone actions on liver metabolism during chronic fatty liver disease and diabetes. While working on these aspects, earlier I showed a new mechanism of Thyroid hormone action where SIRT1-FOXO1 and SIRT1-MTORC2-AKT signaling regulate hepatic gluconeogenesis. Later, I showed that orphan nuclear receptor Estrogen-related receptor alpha (ERRa/ESRRA) is indispensable for thyroid hormone actions on mitochondria, which previously thought to be directly regulated by thyroid hormones. Currently, my research is focusing on the roles of ERRa in chronic fatty liver diseases with special focus on the effects of starvation and fuel utilization.

Education
2011   PhD Biotechnology, Bundelkhand University, Jhansi, U.P. India.
2004     Masters of Science (MSc) Biotechnology, Bundelkhand University, Jhansi, U.P. India.
2002     Bachelors of Science (BSc), Bundelkhand University, Jhansi, U.P. India.

Professional Memberships:
2018-         Present Joined MitoEAGLE Task Group, COST (European Cooperation in Science and Technology)
2017-2021 Early Career member of The Biochemical Society – UK
2017-2021 Early Career member of Federation of European Biochemical Societies (FEBS) – UK
2017-2018 Early Career Member of Endocrine Society – USA 
2017-2021 Post-Doctoral member of American Association for the Advancement of Science (AAAS) 
2017-2020 Post-Doctoral member of The American Society for Cell Biology (ASCB)
2017-         Life member of Indian Science Congress Association (ISCA)
2016-2020 Regular member of American Society for Biochemistry and Molecular Biology (ASBMB)
2014-2015 Associate member of American Thyroid Association (ATA)
2011-         Life member of Biotech Research Society (BRSI) - India 
2011-         Life member of Indian Society of Cell Biology (ISCB)
2011-         Life member of Mitochondria Interest Group (MIG)-National Institutes of Health (NIH)
2011-         Life member of Society for Free Radical Research (SFRR) – India

Other Experience:

2022  Edited a special issue: Sakkiah, S., Lee, K. W., Selvaraj, C., Singh, B. K., eds. Novel Therapeutic Interventions Against Infectious Diseases: COVID-19. Lausanne: Frontiers Media SA. doi: 10.3389/978-2-88974-846-4

2021 Elected as an Associate Editor in peer reviewed journals Frontiers in Molecular Biosciences, and Frontiers in Cell and Developmental Biology.

2021 Invited as Keynote Guest in International Pathology Conference of Victor Babes Institute 2021, Romania.

2020 Invited speaker at OpenTox Virtual Conference 2020, OpenTox Association, Switzerland.

2020 Appointed as panel reviewer by Ministry Of Health/National Medical Research Council Singapore, and National Science Centre Poland to review research proposals for funding opportunities.

2020 Editorial Board Member in peer reviewed journal International Journal of Molecular Sciences.

2018 Invited to participate in ‘International YoungMito 2018’ the 1st International Mitochondria Meeting for Young Scientists (Crosstalk between Molecular and Physiological Functions), Kyoto, Japan.

2015 Appointed reviewer by journals AJP-Endocrinology and Metabolism, Autophagy, Biochimica et Biophysica Acta, FSEB J, Aging-US, Molecular Metabolism, Biochemical Pharmacology, Molecular Carcinogenesis, PLoS ONE, Life Sciences, Theranostics, Cancers, Cells, Journal of Cellular and Molecular Medicine, etc.

2014 Invited speaker at 11th International Workshop on Resistance to Thyroid Hormone and Thyroid Hormone Action, Madrid, Spain.

 

I have a strong and longstanding interest in understanding hepatic metabolism and pathophysiology of metabolic-associated diseases (such as NAFLD/NASH, T2D, obesity) and aging. I also have gained very much interest in extrahepatic manifestations of NASH as it worsens cardiovascular/chronic heart diseases, chronic kidney disease and life expectancy. My recent research work currently is focused on studying hepatic actions of nuclear hormone receptors such as estrogen related receptors (ERRs), thyroid hormone receptors (THRs) and finding therapeutic targets for metabolic diseases and aging. I have found that thyroid hormone (TH) together with ERRalpha, regulates mitochondrial biogenesis, fission, mitophagy and other key mitochondrial processes, thus may be beneficial in NAFLD (Sci Signal, 2018; Nat Rev Endocrinol, 2018; Hepatology, 2020) that are important for mitochondria homeostasis and cell health, and may have implications in NAFLD, T2D and aging. Along with nuclear receptors, targeting interleukin-11 is beneficial in drug induced hepatotoxicity, NAFLD and obesity (Gastroenterology, 2019; Sci. Transl. Med. 2021; Nat. Commun. 2021). Recently, we have also developed a protocol to mimic metabolic effects of aging in mouse hepatic cell line and validated with metabolic and molecular changes appeared in an aged mouse liver (Aging, 2020; Star Protocols 2020). Thus, I have been awarded a national competitive NMRC-OFIRG grant (MOH-OFIRG19may-0002 for the period Jan 2020-Dec 2023) to study the roles of ERRalpha in NAFLD and aging. I previously demonstrated that TH activation of SIRT1 leads to inhibition of MTORC2-AKT signaling that increases nuclear localization of FOXO1 and its activation via SIRT1-mediated deacetylation. This novel mechanism showed that nuclear hormone receptors could directly activate other transcription factors and their target genes through SIRT1 (J Biol Chem, 2016 and 2013; Endocr Rev, 2016, Trends Endocrinol Metab, 2014). Given the large repertoire of protein targets that can be deacetylated by SIRT1, we embarked on acetylome studies to identify proteins that may be regulated by SIRT1 deacetylation. Thus, I was awarded a national competitive NMRC-OFYIRG grant (NMRC/OFYIRG/0002/2016 for the period Aug 2016-Feb 2020), where we identified about a dozen proteins that are deacetylated by SIRT1 in the liver, and FASN appears to be the most promising with respect to metabolism and non-alcoholic fatty liver disease (NAFLD) given its prominent role in fatty acid biosynthesis. On the other note, we also showed how nuclear hormone activates mitochondrial quality control by autophagy, a novel regulation of nuclear hormone action, to regulate energy metabolism (Autophagy, 2015 and 2018; Endocr Rev, 2016). Furthermore, we have also showed that autophagic fat clearance (lipophagy) by natural compounds such as caffeine and epigallocatechin-3-gallate that are active compounds of coffee and green tea, as well as β-adrenergic agonist and antagonist, help to ameliorate fatty liver condition in rodent model of NAFLD and well associated with humans (Hepatology, 2013; PLoS One, 2014). 

Research Support

2020-2023  National Medical Research Council-OFIRG (MOH-000319 (MOH-OFIRG19may-0002)) Title: Targeting hepatic estrogen-related receptor alpha (ESRRA) for activating lysosomal biogenesis and function during non-alcoholic fatty liver disease (NAFLD) and aging.

Role: PI
Funding: SGD1,500,000.00

2018-2021  National Medical Research Council-OFYIRG (NMRC/OFYIRG/0077/2018) Title: Role of novel covalent homocysteine modification of the autophagy protein, Syntaxin 17, in regulating non-alcoholic fatty liver disease (NAFLD) progression.

Role: Collaborator
Funding: SGD300,000.00

2016-2019  National Medical Research Council-OFYIRG (NMRC/OFYIRG/0002/2016) Title: SIRT1 regulation of fatty acid synthase (FASN) acetylation in non-alcoholic fatty liver disease (NAFLD). 

Role: PI
Funding: SGD565,200.00

Research Experience:
2004-2005      Project Assistant, CSIR-National Botanical Research Institute, Lucknow, U.P. 
2005-2007      Junior Research Fellow, CSIR-Indian Institute of Toxicology Research, Lucknow, U.P. 
2007-2010      Senior Research Fellow, CSIR-Indian Institute of Toxicology Research, Lucknow, U.P. 
2011-2015      Post-Doctoral Research Fellow, Duke-NUS Medical School, Singapore 
2016-2017      Senior Research Fellow (Post-Doctoral), Duke-NUS Medical School, Singapore 
2017-present  Assistant Professor, Duke-NUS Medical School, Singapore

Total citations 3261, h-index 30; from: Google Scholaras on Jul’2022):      

Original research in peer-reviewed journals (for last five years)

  1. Tripathi M*, Singh BK*, Zhou J, Tikno K, Widjaja A, Sandireddy R, Arul K, Ghani SABA, Bee GGB, Wong KA, Ho JP, Shekeran SG, Sinha RA, Singh MK, Cook SA, Suzuki A, Lim TR, Cheah CC, Wang J, Xiao RP, Zhang X, Chow PKH, Yen PM. Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing Syntaxin 17 homocysteinylation. J Hepatol. 2022. JHEPAT-D-21-02446R1 (Accepted manuscript) *Share equal authorship
  2. 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. 2022. (Accepted manuscript)
  3. Sakkiah S, Singh BK, Lee KW, Selvaraj C. Editorial: Novel Therapeutic Interventions Against Infectious Diseases: COVID-19. Front Pharmacol. 2022. 13:852078.
  4. Tripathi M., Singh B. K., Liehn E. A., Lim S. Y., Tikno K., Castano-Mayang D., Rattanasopa C., Nilchamd P., Ghania S. A. B. A., Wu Z., Hazwani S., Zhou J., Hernández-Resèndiz S., Crespo-Avilan G. E., Sinha R. A., Farah B. L., Moe K. M., De Silva D. A., Angeli V., Singh M. K., Singaraja R. R., Hausenloy D. J., Yen P. M. Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy. Autophagy 2022. 1-11. doi: 10.1080/15548627.2021.2021494. (Accepted manuscript)
  5. 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. 32(6):725-738.
  6. Rajak S, Gupta P, Anjum B, Raza S, Tewari A, Ghosh S, Tripathi M, Singh BK, Sinha RA. Role of AKR1B10 and AKR1B8 in the pathogenesis of non-alcoholic steatohepatitis (NASH) in mouse. Biochim Biophys Acta Mol Basis Dis. 2022. 1868(4):166319. doi: 10.1016/j.bbadis.2021.166319.
  7. Widjaja A. A., Viswanathan S., Jinrui D., Singh B. K., Tan J., Wei Ting J. G., Lamb D., Shekeran S. G., George B. L., Schafer S., Carling D., Adami E., Cook S. A. Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts. Front Mol Biosci. 2021. 8:740650.
  8. Dasan M. C., Sandireddy R., Bogireddy  H., Tee  N., Ghani S. A. B. A., Singh  B. K., Mackman  N., Singh M. K., Singh  A. Cardiac Tissue Factor Regulates Inflammation, Hypertrophy and Heart Failure in Mouse Model of Type 1 Diabetes. Diabetes. 2021; 70(9):2131-2146.
  9. Bruinstroop E., Zhou J., Tripathi M., Yau W. W., Boelen A., Singh B. K., Yen P. M. Early induction of hepatic deiodinase type 1 inhibits hepatosteatosis during NAFLD progression. Mol Metab. 2021:101266.
  10. Yau W. W., Wong K. A., Zhou J., Thimmukonda N. K., Wu Y., Bay B. H., Singh B. K., Yen P.M. Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue. iScience. 2021;24(5):102434.
  11. Zhou J., Singh B. K., Ho J. P., Lim A., Bruinstroop E., Ohba K., Sinha R. A., Yen P. M. MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophagy 2021;18:1-19.
  12. Widjaja A., Dong J., Adami E., Viswanathan S., Ng B., Pakkiri L. S., Singh B. K., Lim W. W., Zhou J., Shekeran S. G., Tan J., Lim S. Y., Goh. J., Wang M., Holgate R., Hearn A., Yen P. M., Chothani S., Felkin L. E., Dear J. W., Drum C. L., Schafer S., Cook S. Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury. Sci Transl. Med. 2021;13(597):eaba8146.
  13. Dong J., Viswanathan S., Adami E., Singh B. K., Chothani S., Ng B., Lim W. W., Zhou J., Tripathi M., Ko N., Shekeran S. G., Tan J., Yun L., Wang M., Lio P. M., Yen P. M., Schafer S., Cook S., Widjaja A.  Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. Nat. Commun. 2021, 12(1):66.
  14. Singh B. K.*, Tripathi M., Sandireddy R., Tikno K., Zhou J., Yen P. M. Decreased autophagy and fuel switching occur in a senescent hepatic cell model system. Aging (Albany NY) 2020, 12(14):13958-13978. *Corresponding author
  15. Tripathi M., Yen P. M. Singh B. K.* Protocol to generate senescent cell model using AML12 cell line to study hepatic aging. Star Protocols (Cell Press) 2020, 1(2):100064 https://doi.org/10.1016/j.xpro.2020.100064 *Corresponding author
  16. Rajak S., Iannucci L. F., Zhou J., Anjum B., George N., Singh B. K., Ghosh S., Yen P. M., Sinha R. A. Loss of ULK1 attenuates cholesterogenic gene expression in mammalian hepatic cells. Frontiers in Cell and Developmental Biology 2020, 8:523550.
  17. Widjaja A.* Singh B. K.*, Adami E.*, Viswanathan S., Dong J., D’Agostino G. A., Ng B., Lim W. W., Tan J., Paleja B. S.,Tripathi M., Lim S. Y., Shekeran S. G., Chothani S. P., Rabes A., Sombetzki M., Bruinstroop E., Min L. P., Sinha R. A., Albani S., Yen P. M, Schafer S., Cook S. A. Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Non-Alcoholic Steatohepatitis. Gastroenterology. 2019, 157(3):777-792.e14. *Share equal authorship
  18. Zhou W, Ma D, Sun A. X., Tran H. D., Ma D. L., Singh B. K., Zhou J, Zhang J, Wang D, Zhao Y, Yen P. M., Goh E, Tan E. K. PD-linked CHCHD2 mutations impair CHCHD10 and MICOS complex leading to mitochondria dysfunction. Hum Mol Genet. 2019, 28(7):1100-1116.
  19. Singh, B. K.*, Sinha, R. A., Tripathi, M., Mendoza, A., Ohba, K., Sy, J. A. C., Xie, S. Y., Zhou, J., Ho, J. P., Chang, C. Y., Wu, Y., Giguere, V., Bay, B. H., Vanacker, J. M., Ghosh, S., Gauthier, K., Hollenberg, A. N., McDonnell, D. P., and Yen, P. M.* Thyroid hormone receptor and ERRα coordinately regulate mitochondrial fission, mitophagy, biogenesis, and function. Sci Signal 2018, 11 (536): eaam5855 *Corresponding authors
  20. Yau, W. W., Singh, B. K., Lesmana, R., Zhou, J., Sinha, R. A., Wong, K. A., Wu, Y., Bay, B. H., Sugii, S., Sun, L., and Yen, P. M. Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and mTOR-mediated mitophagy. Autophagy 2018, 13:1-20.

     

    Invited reviews in peer-reviewed journals:

  21. Zhou J., Tripathi M., Sinha R. A., Singh B. K., Yen P. M. Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease. Hepatoma Res. 2021;7:11.
  22. Tripathi M., Yen P. M. Singh B. K.* Estrogen related receptor alpha: An under-appreciated potential target for the treatment of metabolic diseases. Int. J. Mol. Sci. 2020, 21(5): pii: E1645. *Corresponding author
  23. Sinha R. A., Bruinstroop E., Singh B. K., Yen P. M. Thyroid hormones and thyromimetics: A new approach to NASH? Hepatology 2020, doi: 10.1002/hep.31204.
  24. Sinha R. A., Rajak S., Singh B. K., Yen P. M. Hepatic lipid catabolism via PPARα-lysosomal crosstalk. Int. J. Mol. Sci. 2020, 21(7). pii: E2391.
  25. Sinha R. A., Bruinstroop E., Singh B. K., Yen P.M. Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists. Thyroid. 2019, 29(9):1173-1191.
  26. Singh, B. K.*, Sinha, R. A., and Yen, P. M.* Novel transcriptional mechanism for regulating metabolism by thyroid hormone. Int. J. Mol. Sci. 2018, 19(10), pii: E3284. *Corresponding author
  27. Sinha, R. A., Singh B. K., Yen P. M. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol. 2018, 14:259-269.
  28. Singh, B. K., Sinha, R. A., Ohba, O., and Yen, P. M. Role of thyroid hormone in hepatic gene regulation, chromatin remodeling, and autophagy. Mol Cell Endocrinol 2017, pii: S0303-7207(17)30105-3.
  29. Sinha, R. A., Singh B. K., Yen P. M. Reciprocal Crosstalk Between Autophagic and Endocrine Signaling in Metabolic Homeostasis. Endocr Rev 2017, 38(1): 69-102.
  30. Singh, B. K., Yen, P. M. A clinician's guide to understanding resistance to thyroid hormone due to receptor mutations in the TRα and TRβ isoforms. Clin Diabetes Endocrinol. 2017, 3:8. doi: 10.1186/s40842-017-0046-z. eCollection 2017.
  31. Shukla S., Saxena S., Singh B. K., Kakkar P. BH3-only protein BIM: An emerging target in chemotherapy. Eur J Cell Biol. 2017, 96 (8), 728-738.
  32. Sinha, R. A.*, Singh, B. K.*, and Yen, P. M. Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism. Trends Endocrin Met 2014, 25, 538-545 *Share equal authorship.
  33. Singh, S., Vrishni, S., Singh, B. K., Rahman, I., and Kakkar, P. Nrf2-ARE stress response mechanism: a control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases. Free Radical Res 2010, 44, 1267-1288.
  34. Kakkar, P., and Singh, B. K.  Mitochondria: a hub of redox activities and cellular distress control. Mol Cell Biochem 2007, 305, 235-253.