Jen-Chywan (Wally) Wang
Molecular Physiology of Steroid Hormones Glucocorticoids and Angiopoietin-like Proteins
The long-term goal of my research is to elucidate mechanisms underlying regulation of metabolic homeostasis. Metabolic disorders are associated with various diseases, such as diabetes, fatty liver diseases, and cancer. My current studies encompass fundamental investigation of physiological processes and novel approaches to therapeutic intervention. My lab focuses on a single regulatory pathway, glucocorticoid signaling, applying a combinatorial approach, including biochemistry, genetics, chemistry and physiology, to dissect its function in metabolic regulation. Glucocorticoids are steroid hormones that play important roles in many aspects of mammalian physiology, including metabolic adaptions under stress conditions. Because of their potent anti-inflammatory and immunomodulatory activities, glucocorticoids are also frequently used to treat inflammatory and autoimmune diseases. Chronic and/or excess glucocorticoid exposure, however, causes unwanted adverse effects that limit the application of glucocorticoids and are associated with a greater risk of comorbidities. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator. We focus on identifying GR-regulated genes that mediate glucocorticoid responses, and transcriptional coregulators that selectively participate in the physiological and pharmacological functions of GR. We also seek to identify signaling pathways that are specifically induced upon chronic glucocorticoid exposure. The goal is not only to advance our molecular understanding of glucocorticoid actions, but also to provide novel insights in designing improved glucocorticoid therapy.
Genome-wide association studies (GWAS) have associated specific genetic variations to diseases. However, how genes containing these variations exert their actions are largely unknown. Another focus in the lab is to identify the mechanisms underlying the actions of these GWAS genes, especially those that encode transcriptional regulators and associate with metabolic disorders and type 2 diabetes. Learning how these genes exert their actions could lead to the development of new therapeutic interventions against metabolic diseases.
- National Taiwan University (B.S. Agricultural Chemistry), Vanderbilt University (Ph.D. Molecular Physiology & Biophysics), University of California San Francisco (Post-doc, Cellular and Molecular Pharmacology)
1. Chen TC, Kuo T, Dandan M, Lee RA, Chang M, Villivalam SD, Liao SC, Costello D, Shankaran M, Mohammed H, Kang S, Hellerstein MK, Wang JC, The Role of Striated Muscle Pik3r1 in Glucose and Protein Metabolism Following Chronic Glucocorticoid Exposure, J Bio Chem, 2021, 296:100395, PMID:33567340, PMCID:PMC8010618
2. Castriota F, Zushin PH, Sanchez SS, Phillips RV, Hubbard A, Stahl A, Smith MT, Wang JC, La Merrill MA, Chronic Arsenic Exposure Impairs Adaptive Thermogenesis in Male C57BL/6J Mice. Am J Physiol Endocrinol Metab, 2020, 318(5): E667-E677, PMID:32045263, PMCID: PMC7272725
3. Castriota F, Rieswijk L, Dahlberg S, La Merrill MA, Steinmaus C, Smith MT, Wang JC, A state-of-the-Science Review of Arsenic’s Effects on Glucose Homeostasis in Experimental Models. Environ Health Perspect, 2020, 128(1):16001. PMID: 31898917, PMCID: PMC7015542
4. Chen TC, Lee RA, Tsai SL, Kanamaluru D, Gray NE, Yiv N, Cheang RT, Fitch MD, Hellerstein, MK, and Wang JC, An Angptl4-Ceramide-PKCx Axis Mediates Chronic Glucocorticoid Exposure-induced Hepatic steatosis and Hypertriglyceridemia. J Biol Chem, 2019, 294(23):9213-9224, PMID:31053639
5. McQueen AE, Koliwad SK, and Wang JC, Fighting Obesity by Targeting Factors Regulate Beige Adipocytes. Curr Opin Clin Nutr Metab Care. 2018 Nov;21(6):437-443. PMID: 30148740; PMCID: PMC6196736.
6. Lee RA, Harris CA, Wang JC, Glucocorticoid Receptor and Adipocyte Biology. Nucl Receptor Res. 2018;5. pii: 101373. PMID: 30310815; PMCID: PMC6177265
7. Lee RA and Wang JC, Angiopoietin-like 4 and Glucocorticoid-induced Insulin Resistance. Oncotarget 2017(8):106143-106144, PMID:28842503
8. McQueen AE, Kanamaluru D, Yan K, Gray NE, Wu L, Li ML, Chang A, Hasan A, Stifler D, Koliwad SK, and Wang JC, The C-terminal Fibrinogen-like Domain of Angiopoietin-like 4 Stimulates Adipose Tissue Lipolysis and Energy Expenditure. J Biol Chem, 2017, 292(39):16122-16134, PMID:28842503
9. Chen TC, Benjamin DI, Kuo T, Lee RA, Li ML, Mar D, Nomura DK, and Wang JC, The Glucocorticoid-Angiopoietin-like 4-Ceramide Axis Induces Insulin Resistance through PP2A and PKCζ. Science Signaling, 2017(10), eaai7905. PMID:28743803
10. Kuo T, Chen TZ, Lee RA, Nguyen N, Broughton AE, Zhang D, and Wang JC, Pik3r1 is Required for Glucocorticoid-induced Perilipin 1 Phosphorylation in Lipid droplet for Adipocyte Lipolysis. Diabetes, 66(6):1601-1610. PMID:28292967
11. Boortz KA, Syring KE, Lee RA, Dai C, Oeser J, McGuinness OP, Powers AC, Wang JC, and O’Brien RM, G6PC2 Modulates the Effects of Dexamethasone on Fasting Blood Glucose and Glucose Tolerance, Endocrinology, 157(11):4133-4145. PMID:27653037.
12. Boortz KA, Syring KE, Dai C, Pound LD, Oeser J, Jacobson DA, Wang JC, McGuinness OP, Powers AC, and O’Brien RM, G6PC2 Evolved to Modulate Insulin Secretion in Response to Stress, Endocrinology, 157(8):3002-3008. PMID:27300767
13. Kuo T, Liu PH, Chen TZ, New J, Wang JC, Transcriptional Regulation of FoxO3 Gene by Glucocorticoids in Murine Myotubes. Am J Physiol Endocrinol Metab, 2016, 310:572-585. PMID:24565756
14. Kuo T, McQueen A, Chen TZ and Wang JC, Regulation of Glucose Homeostasis by Glucocorticoids. Adv Exp Med Biol, 2015, 872:99-126, PMID:26215992
15. Granner DK, Wang JC, and Yamamoto KR, Regulatory Actions of Glucocorticoid Hormones: from Organisms to Mechanisms. Adv Exp Med Biol, 2015, 872:3-31, PMID:26215988
16. Ou CY, Chen TZ, Lee JV, Wang JC*, Stallcup MR*, Coregulator CCAR1 Positively Regulates Adipocyte Differentiation through the Glucocorticoid Signaling Pathway. J Biol Chem, 2014, 289(24):17078-86 (*Co-corresponding authors). PMID:24811171
17. Kuo T, Chen TZ, Yan S, Foo F, Ching C, McQueen A, Wang JC, Repression of Glucocorticoid-stimulated Angiopoietin-like 4 (Angptl4) Gene Transcription by Insulin. J Lipid Res, 2014, 55(5):919-28. PMID:24565756
18. Poole DP, Lee M, Tso P, Bunnett NW, Yo SJ, Lieu T, Shiu A, Wang JC, Nomura DK, Aponte GW, Feeding-dependent activation of enteric cells and sensory neurons by lymphatic fluid: evidence for a neurolymphocrine system. Am J Physiol Gastrointest Liver Physiol. 2014, 306(8):G686-98. PMID:24578341
19. Kuo T, Harris C, Wang JC, Metabolic Functions of Glucocorticoid Receptor in Skeletal Muscle. Mol Cell Endocrinol, 2013, 380(1-2):79-88. PMID: 23523565
20. Wang JC, Gray NE, Kuo T, and Harris C, Regulation of Triglyceride Metabolism by Glucocorticoid Receptor. Cell Biosci, 2012, 2:19. PMID:22640645
21. Koliwad SK, Gray NE, and Wang JC. Angiopoietin-like 4 (Angptl4): A Glucocorticoid-Dependent Gatekeeper of Fatty Acid Flux During Fasting. Adipocyte, 2012, 1:182-7. PMID: 23700531
22. Kuo T, Lew M, Mayba O, Harris CA, Speed, T, and Wang JC, Genome-wide Analysis of Glucocorticoid Receptor Binding Regions in Myotubes Reveal Gene Network Modulating Insulin Signaling Pathway. PNAS, 2012, 109:11160-5. PMID:22733784
23. Gray NE, Lam L, Yang, K, Zhou A, Koliwad, SK, Wang JC, Angiopoietin-like 4 (Angptl4) is A Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes. J Biol Chem, 2012 287:8444-56. PMID:22267746
24. Yu CY, Mayba O, Lee JV, Tran J, Harris C, Speed T, and Wang JC, Genome-wide Analysis of Glucocorticoid Receptor Binding Regions in Adipocytes Reveal Gene Network Involved in Triglyceride Homeostasis, PLoS ONE, 2010, 5(12):e15188. PMID:21187916.
25. Shipp LE, Lee JV, Yu CY, Pufall M, Zhang P, Scott DK, Wang JC, Transcriptional Regulation of Human Dual Specificity Protein Phosphatase 1 (DUSP1) Gene by Glucocorticoids, PLoS ONE, 2010, 5(10):e13754. PMID:21060794
26. Roohk DJ, Varady KA, Turner SM, Emson CE, Gelling RW, Shankaran M, Lindwall G, Shipp LE, Scanlan TS, Wang JC, Hellerstein MK. Differential in vivo effects on target pathways of a novel arylpyrazole glucocorticoid receptor modulator compared to prednisolone. J Pharmacol Exp Ther. 2010 Jan 11. PMID:20065017
27. Koliwad SK, Kuo T, Shipp LE, Gray NE, Backhed F, So AY, Farese RV Jr, Wang JC. Angiopoietin-like 4 (ANGPTL4/FIAF) is a direct glucocorticoid receptor target and participates in glucocorticoid-regulated triglyceride metabolism. J Biol Chem. 2009 284:25593-601