Department of Molecular Medicine
 

[ default picture ] Mengwei  Zang, M.D.Ph.D.

Associate Professor


Profile and Contact Information | Research | Laboratory


RESEARCH

 

Research Program

The overall goal of research in the Zang laboratory is to understand the fundamental regulation of nutrient sensing network in lipid metabolism and insulin action as well as to translate these basic research findings into potential targeted therapies for obesity, type 1 and type 2 diabetes, non-alcoholic liver disease (NAFLD), and alcoholic liver disease (ALD). Major research interests include identifying novel nutrient sensing pathways involved in the regulation of cell metabolism and insulin sensitivity; discovering the mechanisms by which novel hepatocyte-secreted molecules alter fuel metabolism and insulin action; and determining the molecular mechanisms that make obesity a risk factor for type 2 diabetes. Zang laboratory employs a variety of approaches, such as protein kinase/phosphorylation, gene regulation, in vivo adenoviral gene delivery, genetic knockout mice, and pharmacological approaches. Her work has had a major impact on understanding the regulation and function of master nutrient sensors, such as AMP-activated protein kinase, the NAD+-dependent deacetylase SIRT1, vitamin A-related retinoic acid receptor, and the recently identified hepatocyte-derived hormone fibroblast growth factor 21 (FGF21). Her work has demonstrated that pharmacological activation of AMPK by polyphenols or metformin can phosphorylate sterol regulatory element-binding protein (SREBP), a key lipogenic factor in the liver, suppress SREBP-dependent lipogenesis in hepatocytes, and slow the progression of hepatic steatosis and aortic atherosclerosis in obesity-induced insulin resistance and diabetes. In addition, Zang laboratory has established a critical role of the FGF21 pathway in mediating liver SIRT1 actions on lipid hemostasis and whole-body energy balance. Her laboratory’s studies have also proposed a critical role of the liver as an endocrine organ and led to the discovery of the hepatocyte-secreted protein FGF21 action in the regulation of the liver-adipose tissue crosstalk and energy balance. Studies from her laboratory have substantially contributed to the current pharmaceutical interest in AMPK, SIRT1, and FGF21 as promising drug targets for treating type 2 diabetes and NAFLD.

Zang Lab Work

 

Selected Publications

  1. Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, Xu XJ, Han J, Yan Y, Yang Q, Li Q, Zang M. AMPK activation by metformin suppresses abnormal adipose tissue extracellular matrix remodeling and ameliorates insulin resistance in obesity. Diabetes. 2016; 65:2295-2310. PMCID: PMC4955985.


  2. Ramirez T, Li YM, Yin S, Xu MJ, Feng D, Zhou Z, Zang M, Mukhopadhyay P, Varga ZV, Pacher P, Gao B, Wang H. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating Sirtuin 1 expression. J Hepatol. 2016 Nov 18. pii: S0168-8278(16) 30651-1. doi: 10.1016/j.jhep.2016.11.004.


  3. Han J, Weisbrod RM, Shao D, Watanabe Y, Yin X, Bachschmid MM, Seta F, Janssen-Heininger YM, Matsui R, Zang M, Hamburg NM, Cohen RA. The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells. Redox Biology. 2016; 306-319. doi: 10.1016/j.redox.2016.09.003. PMCID: PMC5045950.


  4. Gong Q, Hu Z, Zhang F, Cui A, Chen X, Jiang H, Gao J, Chen X, Han Y, Liang Q, Ye D, Shi L, Eugene Chin Y, Wang Y, Xiao H, Guo F, Liu Y, Zang M, Xu A, Li Y. Fibroblast Growth Factor 21 Improves Hepatic Insulin Sensitivity by Inhibiting Mammalian Target of Rapamycin Complex 1. Hepatology, 2016; Feb 29. doi: 10.1002/hep.28523. [Epub ahead of print].


  5. Li XY, Kover K, Heruth D, Watkins DJ, Moore WV, Zang M, Clements M, and Yun Yan. New insight into metformin action: regulation of ChREBP and FoXO1 activities in endothelial cells. Molecular Endocrinology, 2015; 29:1184-94.


  6. Li Y, Wong K, Giles A, Lee JW, Jiang J, Adams AC, Kharitonenkov A, Yang Q, Gao B, Guarente L, Zang M. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology, 2014; 146: 539-549. PMCID: PMC4228483.


  7. Li Y, Xu S, Jiang B, Cohen RA, Zang M. Activation of sterol regulatory element binding protein and NLRP3 inflammasome in atherosclerotic lesion development in diabetic pigs. PLoS One, 2013; 8: e67532. doi:10.1371. PMCID: 3692453.


  8. Li Y, Wong K, Walsh K, Gao B, Zang M. Retinoic acid receptor β stimulates hepatic induction of fibroblast growth factor 21 to promote fatty acid oxidation and control whole-body energy homeostasis in mice. Journal of Biological Chemistry, 2013; 288: 10490-10540, PMCID: 3624431.


  9. Li Y, Xu S, Mihaylova M, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin resistant mice. Cell Metabolism, 2011; 13: 376-388. PMCID: 3086578.


  10. Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, Donmez G, Li J, Luo Z, Walsh K, Guarente L, Zang M. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB Journal, 2011; 25: 1664-1679. PMCID: 3079300.


  11. Xu S, Jiang B, Hou X, Shi C, Bachschmid M, Zang M, Verbeuren TJ, Cohen RA. High-fat diet increases and the polyphenol, S17834, decreases acetylation of the SIRT1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice. Journal of Cardiovascular Pharmacology, 2011; 58: 263-271. PMCID: PMC3168693.


  12. Ponugoti B, Xiao Z, Wu S, Chiang C, Zang M, Veenstra TD, Kemper J Kim. SIRT1 deacetylates and inhibits SREBP-1c activity in hepatic lipid metabolic regulation. Journal of Biological Chemistry, 2010; 285: 33959–33970. PMCID: PMC2962496.


  13. Luo Z, Zang M, Wen G. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncology, 2010; 6: 457-470. PMCID: PMC2854547.


  14. Wang J, Ma H, Tong C, Zhang H, Lawlis GB, Li Y, Zang M, Ren J, Nijland MJ, Ford SP, Nathanielsz PW, Li J. Overnutrition and maternal obesity in sheep pregnancy alter the JNK-IRS-1 signaling cascades and cardiac function in the fetal heart. FASEB Journal, 2010; 24: 2066-2076. PMCID: PMC2874473.


  15. Tao R, Gong J, Luo X, Zang M, Guo W, Wen R, Luo Z. AMPK exerts dual regulatory effects on the PI3K pathway. Journal of Molecular Signaling, 2010; 5(1):1. doi: 10.1186/1750-2187-5-1. PMCID: PMC2848036.


  16. Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren TJ, Cohen RA, Zang M. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-Activated protein kinase. Journal of Biological Chemistry, 2008; 283: 20015-20026. PMCID: PMC2459285.


  17. Zang M, Gong J, Luo L, Zhou J, Xiang X, Huang W, Huang Q, Luo X, Olbrot M, Peng Y, Chen C, Luo Z. Characterization of S338 phosphorylation for Raf-1 activation. Journal of Biological Chemistry, 2008; 283: 31429-31437. PMCID: PMC2581588.


  18. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherogenesis in diabetic LDL receptor-deficient mice. Diabetes, 2006; 55: 2180-2191. PMID: 16873680.


  19. Zuccollo A, Shi C, Mastroianni R, Maitland KA, Weisbrod RM, Zang M, Xu S, Cayatte A, Corda S, Lavielle G, Verbeuren TJ, Cohen RA. The thromboxane A2 receptor antagonist, S18886, prevents enhanced atherogenesis caused by diabetes mellitus. Circulation, 2005; 112: 3001-3008. PMID: 16260636.


  20. Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB, Cohen RA. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. Journal of Biological Chemistry, 2004; 279: 47898-47905. PMID: 15371448.


  21. Zang M, Dong M, Pinon DI, Ding X, Hadac EM, Miller LJ. Spatial approximation between a photolabile residue in position 13 of secretin and the amino-terminal tail of the secretin receptor. Molecular Pharmacology, 2003; 63: 993-1001. PMID: 12695527.


  22. Dong M, Li Z, Zang M, Pinon DL, Lybrand TP, Miller LJ. Spatial approximation between two residues in the mid-region of secretin and the amino terminus of its receptor. Journal of Biological Chemistry, 2003; 278: 48300-48312. PMID:14500709.


  23. Xiang X, Zang M, Waelde CA, Wen R, Luo Z. Phosphorylation of S338SYY341 regulates specific interaction between Raf-1 and MEK1. Journal of Biological Chemistry, 2002; 277: 44996-45003. PMID: 12244094.


  24. Zang M, Hayne C, Luo Z. Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1. Journal of Biological Chemistry, 2002; 277: 4395-4405. PMID: 11733498.


  25. Huang YZ, Zang M, Xiong WC, Luo Z, Mei L. Erbin suppresses the MAP kinase pathway: Down-regulation of AChR epsilon-subunit gene transcription. Journal of Biological Chemistry, 2002; 278: 1108-1114. PMID: 12379659.


  26. Dong M, Zang M, Pinon DI, Li Z, Lybrand TP, Miller LJ. Interaction among four residues distributed through the secretin pharmacophore and a focused region of the secretin receptor amino terminus. Molecular Endocrinology, 2002; 16: 2490-2501. PMID: 12403838.


  27. Zang M, Waelde CA, Xiang X, Rana A, Wen R, Luo Z. Microtubule integrity regulates Pak leading to Ras-independent activation of Raf-1. Journal of Biological Chemistry, 2001; 276: 25157-25165. PMID: 11274179.


  28. Dong M, Asmann YW, Zang M, Pinon DI, Miller LJ. Identification of two pairs of spatially approximated residues within the carboxyl-terminus of secretin and its receptor. Journal of Biological Chemistry, 2000; 275: 26032-26039. PMID: 10859300.