Kezhong Zhang, PhD

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 (PM_2.5)-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 transcriptional factor or stress hormone (hepatokine) in 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 PM_2.5 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.

Mentoring

Accepting new M.S. students in 2024-2025

Accepting new Ph.D. students in 2024-2025

Selected Publications

Kim H, Chen Q, Ju D, Purandare N, Chen X, Samavati L, Li L, Zhang R, Grossman LI, Zhang K. 2024. ER-tethered Stress Sensor CREBH Regulates Mitochondrial Unfolded Protein Response to Maintain Energy Homeostasis. Proc Natl Acad Sci USA 2024, 121(49):e2410486121.

Song Z, Thepsuwan P, Hur W, Torres M, Wu S, Wei X, Tushi N, Wei J, Ferraresso F, Paton A, Paton J, Zheng Z, Zhang K, Fang D, Kastrup C, Jaiman S, Flick M, Sun S. 2024. Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. Nature Commun. 2024, 15(1):9244.

Liang X, Hou X, Bouhamdan M, Sun Y, Song Z, Rajagopalan C, Jiang H, Wei H, Song J, Yang D, Guo Y, Zhang Y, Mou H, Zhang J, Chen YE, Sun F, Jin J #, Zhang K #, Xu J #. 2024. Sotagliflozin Attenuates Liver Associated Disorders in Cystic Fibrosis Rabbits. JCI Insight  2024, 9(6): e165826. [# Corresponding authors].

Song Z, Wang K-W, Hagar H-T, Chen H-R, Kuan C-Y, Zhang K #, Kuo M-H #. 2024. Hyperphosphorylated tau Inflicts Intracellular Stress Responses That Are Mitigated by Apomorphine. Molecular Neurobiology. 2024 May; 61(5): 2653-2671. [# Corresponding authors].

Kim H, Song Z, Zhang R, Davies BSJ, Zhang K. 2023. A Hepatokine Derived from the ER protein CREBH Promotes Triglyceride Metabolism by Stimulating Lipoprotein Lipase Activity. Science Signal. 16(768):eadd6702.

Wang J., Xu L., Kim H., Qiu Y., Zhang K. 2023. Boosting UPR Transcriptional Activator XBP1 Accelerates Acute Wound Healing. PNAS Nexus  2023, 2(3):pgad050.

Wu Q, Liang X, Hou X, Song Z, Bouhamdan M, Qiu Y, Koike Y, Rajagopalan C, Wei H, Jiang H, Hish G, Zhang J, Chen YE, Jin J, Xu J #, Zhang K #, Sun F. 2022. Cystic Fibrosis Rabbits Develop Spontaneous Hepatobiliary Lesions and CFLD-like Phenotypes. PNAS Nexus, 2(1):pgac306. [# Corresponding authors].

Wang S, Yang M, Li P, Sit J, Wong A, Rodrigues K, Lank D, Zhang D, Zhang K, Yin L, and Tong X. 2022. High-fat diet-induced deSUMOylation of E4BP4 promotes lipid droplet biogenesis and liver steatosis in mice. Diabetes  72(3):348-361.

Thepsuwan P, Bhattacharya A, Song Z, Hippleheuser S, Feng S, Wei X, Das N, Sierra M, Wei J, Fang D, Huang Y, Zhang K, Shah Y, Sun S. 2023. Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin. Proc Natl Acad Sci USA 120(2):e2212644120.

Fu Z., Kim H., Morse P.T., Lu M., Huttemann M., Cambronne X.A., Zhang K.#, Zhang R#. 2022. The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions. Metabolism  2022, 135: 155275. [# Corresponding authors].

Kim H, Fu Z, Yang Z, Song Z, Shamsa EH, Yumnamcha T, Sun S, Liu W, Ibrahim A, Qi N, Zhang R, Zhang K. 2022. The Mitochondrial NAD Kinase Functions as a Major Metabolic Regulator Upon Increased Energy Demand. Mol Metabolism 2022, 64: 101562.

Kujawa M, O'Meara M, Li H, Xu L, Meda Venkata SP, Nguyen H, Minjares M, Zhang K, Wang JM. 2022. MicroRNA-466 and microRNA-200 increase endothelial permeability in hyperglycemia by targeting Claudin-5. Molecular Therapy - Nucleic Acids. 2022, 29:259-271.

Loka RS, Song Z, Sletten ET, Kayal Y, Vlodavsky I, Zhang K#, Nguyen HM#. 2022. Heparan Sulfate Mimicking Glycopolymer Prevents Pancreatic β Cell Destruction and Suppresses Inflammatory Cytokine Expression in Islets under the Challenge of Upregulated Heparanase. ACS Chem Biol. 2022;17:1387-1400. [# Corresponding authors].

Zhang Y, Gui M, Wang Y, Mani N, Chaudhuri S, Gao B, Li H, Kanwar YS, Lewis SA, Dumas SN, Ntambi JM, Zhang K, Fang D. 2021. IRE1α-mediated monounsaturated fatty acid synthesis drives B cell differentiation and lupus-like autoimmune disease. Arthritis Rheumato. 2021 Jun 8. doi: 10.1002/art.41883. 

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. Mol 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]

Aras S, Purandare N, Gladyck S, Somayajulu-Nitu M, Zhang K, Wallace DC, Grossman LI. 2020. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms. Proc Natl Acad Sci USA. 117(50): 32056-32065.

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. [# corresponding authors].

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. Gastroenterology. 2018 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.
  
 

Honors and Recognitions

Distinguished Professor, Wayne State University (2024- )

Wayne State University School of Medicine Outstanding Research Achievement Award (2022)

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

Wayne State University Academy of Scholars (2020- )

Charles H. Gershenson Distinguished Faculty Fellow, Wayne State University (2019)

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 Outstanding 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)