Kezhong Zhang, PhD

Kezhong Zhang, PhD

Professor of Molecular Medicine and Genetics and of Biochemistry, Microbiology, and Immunology
Scott Hall, Rm 3202
540 E. Canfield Avenue
Detroit, MI 48201
313-577-2669
kzhang@med.wayne.edu
 

Education

Fudan University, PhD, 1998

Research Focus

     Research in this laboratory is focused on cellular stress responses originated from the endoplasmic reticulum (ER) and/or mitochondria that modulate inflammation and metabolism that are associated with metabolic disease, autoimmune disease, and cancer. The ER is an organelle that is primarily recognized as a compartment for protein folding and assembly, a pool of intracellular calcium, and a site for lipid and sterol biosynthesis. Physiological states that increase protein-folding demand, or stimuli that disrupt protein folding reactions, create an imbalance between the protein-folding load and capacity of the ER. This can cause accumulation of unfolded or misfolded proteins in the ER lumen -a condition referred to “ER stress”. To ensure the fidelity of protein folding and to handle the accumulation of unfolded or misfolded proteins, the ER has evolved a group of signal transduction pathways collectively termed “Unfolded Protein Response (UPR)” to alter transcriptional and translational programs. The UPR is a critical regulator in the initiation and progression of a variety of human diseases. Research projects in the Zhang laboratory include: 1) regulation of hepatic energy metabolism by ER stress-inducible transcriptional activators; 2) roles and mechanisms for the UPR transducer IRE1a in rheumatoid arthritis and lupus; 3) airborne particulate matter (PM2.5)-induced cellular stress responses and their effects on non-alcoholic steatohepatitis (NASH) and type-2 diabetes; and 4) roles of ER lipid-raft proteins and UPR transducers in breast cancer malignancy maintenance and therapy resistance.

     The major accomplishments by the Zhang lab include: 1) revealing the liver-enriched stress sensor CREBH and its functions and molecular mechanisms as a key transcriptional regulator of energy metabolism under the circadian clock or metabolic stress; 2) defining the pathophysiological roles and mechanisms for the primary ER stress sensor IRE1α in B cell development, hepatic lipid metabolism, and macrophage inflammation; 3) uncovering stress mechanisms by which air pollution induces non-alcoholic fatty liver disease (NAFLD), and revealing that the liver is a major target organ of fine airborne particulate matter PM2.5 that is responsible for air pollution-induced NAFLD and Type-2 diabetes in non-obese individuals; 4) identifying the ER lipid-raft protein ERLIN2 as an unconventional oncogenic factor that facilitates luminal breast cancer cell cycle progression, lipid metabolism, and aggressive malignancy.

Selected Publications

Kim H, Wei J, Song Z, Mottillo E, Samavati L, Zhang R, Li L, Chen X, Jena BP, Lin JD, Fang D, Zhang K. 2021. Regulation of Hepatic Circadian Metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα Transcriptional Program. Molecular Metabolism 2021 Feb 13;49:101192

Hetz C#, Zhang K#, Kaufman R#. 2020. Mechanisms, regulation and functions of the unfolded protein response. Nature Rev. Mol. Cell Biol. 2020 Aug;21(8):421-438. [# corresponding authors]

Zhang K, Liu H, Song Z, Jiang Y, Kim H, Samavati L, Nguyen HM, Yang ZQ. The UPR Transducer IRE1 Promotes Breast Cancer Malignancy by Degrading Tumor Suppressor microRNAs. iScience. 2020 Aug 25;23(9):101503

Li, R., Wang Y., Chen R., Gu W., Zhang L., Gu J., Wang Z., Liu Y., Sun Q., Zhang K., Liu C. 2020. Ambient fine particulate matter disrupts hepatic circadian oscillation and lipid metabolism in a mouse model. Environmental Pollution 262:114179

Li R, Sun Q, Lam SM, Chen R, Zhu J, Gu W, Zhang L, Tian H, Zhang K, Chen LC, Sun Q, Shui G, Liu C. 2020. Sex-dependent effects of ambient PM2.5 pollution on insulin sensitivity and hepatic lipid metabolism in mice. Part Fibre Toxicol. 17(1):14.

Kim H, Williams D, Qiu Y, Song Z, Yang Z, Kimler V, Goldberg A, Zhang R, Yang Z, Chen X, Wang L, Fang D, Lin JD, Zhang K. Regulation of hepatic autophagy by stress-sensing transcription factor CREBH. FASEB J. 2019 Jul;33(7):7896-7914

Talreja J, Talwar H, Bauerfeld C, Grossman LI, Zhang K, Tranchida P, Samavati L. HIF-1α regulates IL-1β and IL-17 in sarcoidosis. Elife 2019 May 1;8. pii: e44519

Li H, O'Meara M, Zhang X, Zhang K, Seyoum B, Yi Z, Kaufman RJ, Monks TJ, Wang JM. Ameliorating Methylglyoxal-Induced Progenitor Cell Dysfunction for Tissue Repair in Diabetes. Diabetes 2019 Jun;68(6):1287-1302.

Wei, J., Yuan, Y., Wang, Y., Zhang, Y., Xu, Y., Yang, Z., Li, F., Gao, B., Jin, C., Melo-Cardenas, J., Chen, L., Pan, H., Wang, J., He, F., Zhang, K.#, Fang, D.#  Hrd1-ERAD controls the hepatokine FGF21 production through K27-linked polyubiquitination of CREBH. EMBO J. 2018 Nov 15;37(22). pii: e98942. [# corresponding authors].

Wei, J., Yuan, Y., Xu, Y., Zhang, Y., Wang, Y., Peek, C.B., Yang, Y., Gao, B., Jin, C., Melo-Cardenas, J., Zhang, K., Wang, J., He, F., Fang, D. ER-associated ubiquitin ligase HRD1 is a therapeutic target for high-fat diet-induced metabolic syndrome. Nat Commun. 2018 Sep 10;9(1):3659.

Bhattacharya, A., Sun, S., Wang, H., Liu, M., Long, Q., Yin, L., Kersten, S., Zhang, K., Qi, L. Hepatic Sel1L-Hrd1 ERAD manages FGF21 levels and systemic metabolism via CREBH. EMBO J. 2018 Nov 15;37(22). pii: e99277. 

Wang JM, Qiu Y, Yang Z, Kim H, Qian Q, Sun Q, Zhang C, Yin L, Fang D, Back SH, Kaufman RJ, Yang L, Zhang K. Inositol Requiring Enzyme 1 Prevents Hepatic Steatosis through Processing microRNAs. Science Signal. 2018 May 15;11(530). pii: eaao4617.

Zhang, P., Kuang, H., He, Y., Idiga, S., Li, S., Chen, Z., Yang, Z., Cai, X., Zhang, K., Potthoff, M., Xu,
Y., Lin, J. NRG1-Fc improves metabolic health via dual hepatic and central action. JCI Insight. 2018, 3(5). pii: 98522.

Zhang, K.#, Kim, H., Fu, Z., Qiu, Y., Yang, Z., Wang, J., Zhang, D., Tong, X., Yin, L., Li, J., Wu, J., Qi, N.R., Houten, S.M., Zhang, R.#. Deficiency of the mitochondrial NAD kinase causes stress-induced non-alcoholic steatohepatitis. Gastroenterology2018 Jan;154(1):224-237. [# corresponding authors].

Kim H, Zheng Z, Walker PD, Kapatos G, Zhang K. CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis. Mol Cell Biol. 2017 Jun 29;37(14). [Cover Story].
 
Wang JM, Qiu Y, Yang ZQ, Li L, Zhang K. Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs. Diabetes. 2017 Jan;66(1):177-192.
 
Zheng Z, Kim H, Qiu Y, Chen X, Mendez R, Dandekar A, Zhang X, Zhang C, Liu AC, Yin L, Lin JD, Walker PD, Kapatos G, Zhang K. CREBH Couples Circadian Clock with Hepatic Lipid Metabolism. Diabetes. 2016 Nov;65(11):3369-3383.
 
Zheng Z, Zhang X, Wang J, Dandekar A, Kim H, Qiu Y, Xu X, Cui Y, Wang A, Chen LC, Rajagopalan S, Sun Q, Zhang K. Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models. J Hepatol. 2015 Dec;63(6):1397-404.
 
Kim H, Mendez R, Chen X, Fang D, Zhang K. Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism. Mol Cell Biol. 2015 Dec;35(24):4121-34.
 
Zhang X, Cai J, Zheng Z, Polin L, Lin Z, Dandekar A, Li L, Sun F, Finley RL Jr, Fang D, Yang ZQ, Zhang K. A novel ER-microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression. Cell Discovery. 2015 Sep 8;1:15024.
 
Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, Zhang K. Liver-Enriched Transcription Factor CREBH Interacts with Peroxisome Proliferator-Activated Receptor α to Regulate Metabolic Hormone FGF21. Endocrinology. 2014, 155(3):769-82.
 
Zheng Z, Xu X, Zhang X, Wang A, Zhang C, Hüttemann M, Grossman LI, Chen LH, Rajagopalan S, Sun S, Zhang, K. 2013. Exposure to Ambient Particulate Matter Induces a NASH-like Phenotype and Impairs Hepatic Glucose Metabolism in an Animal Model. J. Hepatol. 2013, 58: 148-154.
 
Qiu Q, Zheng Z, Chang L, Zhao YS, Tan C, Dandekar A, Zhang Z, Lin Z, Gui M, Li X, Zhang T, Kong Q, Li H, Chen S, Chen A, Kaufman RJ, Yang WL, Lin HK, Zhang D, Perlman H, Thorp E, Zhang K*, Fang D*. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J. 2013 Sep 11;32(18):2477-90. (* corresponding author).
 
Zhang C, Wang G, Zheng Z, Maddipati KR, Zhang X, Dyson G, Williams P, Duncan SA, Kaufman RJ, Zhang K. ER-tethered Transcription Factor CREBH Regulates Hepatic Lipogenesis, Fatty Acid Oxidation, and Lipolysis upon Metabolic Stress. Hepatology 2012, 55 (4): 1070-1082.
 
Zhang, K.*, Wang, S., Malhotra, J., Hassler, J.R., Back, S.H., Wang, G., Chang, L., Xu, W., Miao, H., Leonardi, R., Chen, E.Y., Jackowski, S., and Kaufman R.J.* 2011. The Unfolded Protein Response Transducer IRE1a Prevents ER Stress-Induced Hepatic Steatosis. EMBO J 30(7):1357-75. * Corresponding author.
 
Laing, S., Wang, G., Briazova, T., Zhang, C., Wang, A., Zheng, Z., Gow, A., Chen, A.F., Rajagopalan, S., Chen, L.C., Sun, Q., Zhang, K. 2010. Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues. Am J Physiol Cell Physiol. 299(4):C736-749. # Editorial on this article in AJ P Cell Physiol. 299:C727-C728.
 
Malhotra, J.D., Miao, H., Zhang, K., Wolfson, A., Pennathur, S., Pipe, S.W., Kaufman, R.J. 2008. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci USA 105 (47):18525-18530.
 
Luebke-Wheeler J, Zhang K, Battle M, Si-Tayeb K, Garrison W, Chhinder S, Li J, Kaufman RJ, Duncan SA. 2008. Hepatocyte nuclear factor 4a is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of CREB-H. Hepatology 48(4):1242-1250.
 
Kurachi, S., Huo, J., Ameri, A., Zhang, K., Yoshizawa, A., Kurachi, K. 2009. An Age Related Homeostasis Mechanism is Essential for Spontaneous Amelioration of Hemophilia B Leyden. Proc Natl Acad Sci USA 106 (19):7921-7926.
 
Zhang, K., Kaufman, R.J. 2008. From endoplasmic-reticulum stress to the inflammatory response. Nature 454(7203):455-462.
 
Zhang, K., Shen, X., Wu, J., Sakaki, K., Saunders, T., Rutkowski, D.T., Back, S.H., Kaufman, R.J. 2006. Endoplasmic Reticulum Stress Activates Cleavage of CREBH to Induce a Systemic Inflammatory Response. Cell 124: 587-599.
 
Zhang, K., Wong, H.N., Song, B., Miller, C.N., Scheuner, D., Kaufman, R.J. 2005. The unfolded protein response sensor IRE1a is required at 2 distinct steps in B cell lymphopoiesis. J. Clin. Invest. 115 (3): 268-281.
 
Hsu, L.H., Park, J.M., Zhang, K., Luo, J.L., Maeda, S., Kaufman, R.J., Eckmann, L., Guiney, D.G., Karin, M. 2004. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428 (6980): 341-345.
  
Zhang, K., Kurachi, S., Kurachi, K. 2002. Genetic mechanisms of age regulation of protein C and blood coagulation. J. Biol. Chem. 277 (6): 4532-4540.
 

Honors and Recognitions

Kamran S. Moghissi, M.D., Endowed Faculty Award in Basic Science Teaching (2020)

Wayne State University Academy of Scholars

Charles H. Gershenson Distinguished Faculty Fellow, Wayne State University

Distinguished Faculty, Wayne State University School of Medicine (2017)

College Research and Teaching Excellent Awards, Wayne State University School of Medicine

Wayne State University Career Development Chair (2016)

Fellow of the American Heart Association  (2012)

National Excellent Doctoral Thesis Award, China (2001)

 

Teaching

Molecular Organelle Physiology (MGG7040, Course Director & Instructor)

Molecular Biology of Cellular Signaling (MGG7400, Course Director & Instructor)

Interdisciplinary Molecular and Cellular Biology (IBS7015, Instructor)

Metabolism and Disease (MGG7020, Instructor)

Bioinformatics: Theory and Practice (MGG7050, Instructor)

Introduction to Genetics (MGG7015, Instructor)

Mechanisms of Neoplasia: Alterations to Cellular Signaling (CB7460, Instructor)