Yuxia (Lisa) Zhang, PhD
M.D. Wuhan University School of Medicine, China, 1997
M.S. Wuhan University School of Medicine, China, 2000
Ph.D. Wuhan University School of Medicine, China, 2005
Postdoctoral Fellow, University of Utah School of Medicine, 2008-2013
Research Assistant Professor, University of Utah School of Medicine, 01-07/2014
1. Nuclear receptors and transcriptional factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)
NAFLD is becoming a major health concern worldwide. The mechanisms underlying the pathogenesis of NAFLD and disease progression from nonalcoholic fatty liver (NAFL; steatosis without hepatocellular injury) to the more aggressive nonalcoholic steatohepatitis (NASH; steatosis and inflammation with hepatocyte ballooning, with or without fibrosis) remain poorly understood. Exosomes are 50–150 nm vesicles secreted by cells and involved in cell-to-cell communications by transferring signaling molecules. Our recent study interestingly showed that disrupting nuclear receptor small heterodimer partner (Nr0b2, SHP), a critical transcriptional regulator of liver metabolism, activates RNA-binding protein and promotes exosome-mediated stress signaling transduction from hepatocytes to macrophages, exacerbating disease progression from NAFL to NASH. The goal for our research is to understand how nuclear receptors and transcriptional factors regulate stress signals transduction inside and outside of cells during metabolic adaptation and metabolic disease. Our ultimate goal is to develop novel approaches to remodel maladaptation in metabolic disease for therapeutic intervention of NAFLD.
2. RNA-binding protein HuR-mediated signaling in liver carcinogenesis
Hepatocellular carcinoma (HCC) is the major histological type of liver cancer and the second leading cause of cancer mortality worldwide. Our long-term goal is to define the molecular mechanisms underlying hepatocarcinogenesis and develop novel strategies for HCC prevention and treatment. HCC arises exclusively on the background of chronic liver injury and inflammation. Thus, targeting key genes that regulate both inflammation and oncogenic pathways in HCC is an attractive therapeutic approach. RNA-binding protein Hu Antigen R (HuR) controls mRNA turnover and translation of numerous genes involved in inflammation and oncogenic pathways. Our recent study showed that HuR is elevated and activated in human HCC and in mouse HCC developed in Shp-knockout liver. Using a combination of genetic and therapeutic approaches, we are testing our hypothesis that HuR acts as a tumor promoter driving liver carcinogenesis, while HuR-targeted intervention is a novel therapeutic strategy for HCC.
Zou A, Magee N, Deng F, Lehn S, Zhong C, Zhang Y. Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. J Biol Chem. 2018; 293(22): 8656-8671. PMCID: PMC5986206.
Magee N, Zhang Y. Role of early growth response 1 in liver metabolism and liver cancer. Hepatoma Res 2017; 3: 268-77. PMCID: PMC5877465
Deng F, Magee N, Zhang Y. Decoding the Role of Extracellular Vesicles in Liver Diseases. Liver Res. 2017; 1(3): 147-155. PMCID: PMC5851463
Zhang Y. NR0B2. Encyclopedia of Signaling Molecules. 2017, 2nd Edition. Choi S, editor. New York, Springer.
Magee N, Zou A, Zhang Y. Pathogenesis of non-alcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Biomed Res Int 2016; 2016:5170402. PMCID: PMC5086374.
Zou A, Lehn S, Magee N, Zhang Y. New insights into orphan nuclear receptor SHP in liver Cancer. Nucl Receptor Res. 2015; 2. pii: 101162. PMCID: PMC4618403
Zhang Y, Liu C, Barbier O, Smalling R, Tsuchiya H, Lee S, Delker D, Zou A, Hagedorn CH, Wang L. Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci Rep. 2016. 3(6): 20559. PMCID: PMC4738356
Lee SM*, Zhang Y*, Tsuchiya H*, Smalling R, Jetten AM, Wang L. Shp/Npas2 axis in regulating the oscillation of liver lipid metabolism. Hepatology. 2015. 61(2): 497-505. PMCID: PMC4303514. * co-first author.
Zhang Y, Xu N, Xu J, Kong B, Copple B, Grace GL, Wang L. E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network. Hepatology. 2014. 60(3): 919-30. PMCID: PMC4146672.
Zhang Y, Wang L. Characterization of the mitochondrial localization of the nuclear receptor SHP and regulation of its subcellular distribution by interaction with Bcl2 and HNF4α. PLoS One. 2013. 8(7): e68491. PMCID: PMC3706418.
Zhang Y, Andrews GK, Wang L. Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP. Nucleic Acids Res. 2012. 40(11): 4850-60. PMCID: PMC3367194. (Featured article)
Zhang Y, Bonzo JA, Gonzalez FJ, Wang L. Diurnal regulation of the early growth response protein 1 (Egr-1) expression by hepatocyte nuclear factor 4alpha (HNF4a) and small heterodimer partner (SHP) crosstalk in liver fibrosis. J Biol Chem. 2011. 286(34): 29635-43. PMCID: PMC3191004.
Zhang Y, Yang Z, Whitby R, Wang L. Regulation of miR-200c by nuclear receptors PPARα, LRH-1 and SHP. Biochem Biophys Res Commun. 2011. 416(1-2):135-9. PMCID: PMC3248804.
Zhang Y, Wang L. Nuclear receptor SHP inhibition of Dnmt1 expression via ERRγ. FEBS Lett. 2011. 585(9): 1269-75. PMCID: PMC3134389.
Zhang Y, Wang L. Nuclear receptor small heterodimer partner in apoptosis signaling and liver cancer. Cancers (Basel). 2011. 3(1): 198-212. Invited review. PMCID: PMC3756356.
Zhang Y, Hagedorn CH, Wang L. Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta. 2011. 1812(8): 893-908. PMCID: PMC3043166.
Pan X, Zhang Y, Wang L, Hussain M. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab. 2010. 12(2): 174-86. PMCID: PMC2925198.
Zhang Y, Soto J, Park K, Viswanath G, Kuwada S, Abel D, Wang L. Nuclear receptor SHP, a death receptor that targets mitochondria, induces apoptosis and inhibits tumor growth. Mol Cell Biol. 2010. 30(6): 1341-56. PMCID: PMC2832505.
Zhang Y, Xu P, Park K, Choi Y, Moore DD, Wang L. Orphan receptor small heterodimer partner suppresses tumorigenesis by modulating cyclin D1 expression and cellular proliferation. Hepatology. 2008. 48(1): 289-98. PMCID: PMC3800167