Jen-Chywan (Wally) Wang
Molecular Physiology of Steroid Hormones Glucocorticoids and Angiopoietin-like Proteins
Glucocorticoids are steroid hormones that convey their signals thorough an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator, to modulate various aspects of mammalian physiology. Because of their potent anti-inflammatory activity, glucocorticoids are also frequently used to treat various inflammatory diseases. However, excess and/or chronic glucocorticoid exposure causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. The goal of our research is to elucidate the mechanisms underlying the effects of glucocorticoids on metabolic homeostasis and the inflammatory response. Currently, there are three major research topics in the laboratory. First, we have identified a list of GR primary target genes and are currently analyzing their roles in metabolic functions of glucocorticoids. Second, recent studies have shown that certain transcriptional coregulators are selectively involved in the GR-regulated gene transcription. We will identify coregulators that act with GR to specifically exert metabolic or inflammatory responses. This will allow us to target specific coregulators to dissociate the anti-inflammatory functions of glucocorticoids from the adverse metabolic effects. Finally, we aim to elucidate the metabolic functions of angiopoietin-like 4 (Angptl4), a GR primary target gene, which encodes a secreted protein that inhibits extracellular lipoprotein lipase. We have found that Angptl4 also promotes intracellular lipolysis in adipocytes. The mechanism underlying such Angptl4 action and its effect in the regulation of glucose homeostasis are currently being investigated in our laboratory.
1. Chen TZ, 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
2. 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.
3. 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.
4. Chen TZ, Benjamin DI, Kuo T, Lee RA, Li ML, Mar DJ, Costello DE, 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
5. 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
6. Kuo T, Liu PH, Chen TZ, Lee RA, New J, Zhang D, and Wang JC, Transcriptional Regulation of FoxO3 Gene by Glucocorticoids in Murine Myotubes. Am J Physiol Endocrinol Metab, 2016, 310:572-585. PMID:24565756
7. 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
8. 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
9. 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
10. Kuo T, Lew M, Mayba O, Harris CA, Speed, T, and Wang JC, Genome-wide Analysis of Glucocorticoid Receptor Binding Sites in Myotubes Reveal Gene Networks Modulating Insulin Signaling Pathway. PNAS, 2012, 109:11160-5. PMID:22733784
11. Gray NE, Lam L, Yang, K, Zhou A, Koliwad, SK, Wang JC, Angiopoietin-like 4 (Angptl4) Protein is a Physiological Mediator of Intracellular Lipolysis in Murine Adipocytes. J Biol Chem, 2012 287:8444-56. PMID:22267746