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Current Medicinal Chemistry

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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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Research Article

Microarray-based Detection of Critical Overexpressed Genes in the Progression of Hepatic Fibrosis in Non-alcoholic Fatty Liver Disease: A Protein-protein Interaction Network Analysis

Author(s): Ali Mahmoudi, Alexandra E. Butler, Antonio De Vincentis, Tannaz Jamialahmadi and Amirhossein Sahebkar*

Volume 31, Issue 23, 2024

Published on: 19 June, 2023

Page: [3631 - 3652] Pages: 22

DOI: 10.2174/0929867330666230516123028

Price: $65

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Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent cause of chronic liver disease and encompasses a broad spectrum of disorders, including simple steatosis, steatohepatitis, fibrosis, cirrhosis, and liver cancer. However, due to the global epidemic of NAFLD, where invasive liver biopsy is the gold standard for diagnosis, it is necessary to identify a more practical method for early NAFLD diagnosis with useful therapeutic targets; as such, molecular biomarkers could most readily serve these aims. To this end, we explored the hub genes and biological pathways in fibrosis progression in NAFLD patients.

Methods: Raw data from microarray chips with GEO accession GSE49541 were downloaded from the Gene Expression Omnibus database, and the R package (Affy and Limma) was applied to investigate differentially expressed genes (DEGs) involved in the progress of low- (mild 0-1 fibrosis score) to high- (severe 3-4 fibrosis score) fibrosis stage NAFLD patients. Subsequently, significant DEGs with pathway enrichment were analyzed, including gene ontology (GO), KEGG and Wikipathway. In order to then explore critical genes, the protein-protein interaction network (PPI) was established and visualized using the STRING database, with further analysis undertaken using Cytoscape and Gephi software. Survival analysis was undertaken to determine the overall survival of the hub genes in the progression of NAFLD to hepatocellular carcinoma.

Results: A total of 311 significant genes were identified, with an expression of 278 being upregulated and 33 downregulated in the high vs. low group. Gene functional enrichment analysis of these significant genes demonstrated major involvement in extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, and the AGE-RAGE signaling pathway. The PPI network was constructed with 196 nodes and 572 edges with PPI enrichment using a p-value < 1.0 e-16. Based on this cut-off, we identified 12 genes with the highest score in four centralities: Degree, Betweenness, Closeness, and Eigenvector. Those twelve hub genes were CD34, THY1, CFTR, COL3A1, COL1A1, COL1A2, SPP1, THBS1, THBS2, LUM, VCAN, and VWF. Four of these hub genes, namely CD34, VWF, SPP1, and VCAN, showed significant association with the development of hepatocellular carcinoma.

Conclusion: This PPI network analysis of DEGs identified critical hub genes involved in the progression of fibrosis and the biological pathways through which they exert their effects in NAFLD patients. Those 12 genes offer an excellent opportunity for further focused research to determine potential targets for therapeutic applications.

Keywords: Gene expression, Wikipathway, KEGG enrichment, GO ontology, PPI network, hub genes, survival analysis.

« Previous
[1]
Al-Qarni, R.; Iqbal, M.; Al-Otaibi, M.; Al-Saif, F.; Alfadda, A.A.; Alkhalidi, H.; Bamehriz, F.; Hassanain, M. Validating candidate biomarkers for different stages of non-alcoholic fatty liver disease. Medicine, 2020, 99(36), e21463.
[http://dx.doi.org/10.1097/MD.0000000000021463] [PMID: 32898995]
[2]
Pellicano, A.J.; Spahn, K.; Zhou, P.; Goldberg, I.D.; Narayan, P. Collagen characterization in a model of nonalcoholic steatohepatitis with fibrosis; a call for development of targeted therapeutics. Molecules, 2021, 26(11), 3316.
[http://dx.doi.org/10.3390/molecules26113316] [PMID: 34205850]
[3]
Romualdo, G.R.; Da Silva, T.C.; Landi, M.F.; Morais, J.Á.; Barbisan, L.F.; Vinken, M.; Oliveira, C.P.; Cogliati, B. Sorafenib reduces steatosis-induced fibrogenesis in a human 3D co-culture model of non-alcoholic fatty liver disease. Environ. Toxicol., 2021, 36(2), 168-176.
[http://dx.doi.org/10.1002/tox.23021] [PMID: 32918399]
[4]
Zeng, Y.; He, H.; An, Z. Advance of serum biomarkers and combined diagnostic panels in nonalcoholic fatty liver disease. Dis. Markers, 2022, 2022, 1-12.
[http://dx.doi.org/10.1155/2022/1254014] [PMID: 35811662]
[5]
Sahebkar, A.; Sancho, E.; Abelló, D.; Camps, J.; Joven, J. Novel circulating biomarkers for non-alcoholic fatty liver disease: A systematic review. J. Cell. Physiol., 2018, 233(2), 849-855.
[http://dx.doi.org/10.1002/jcp.25779] [PMID: 28063221]
[6]
De Vincentis, A.; Rahmani, Z.; Muley, M.; Vespasiani- Gentilucci, U.; Ruggiero, S.; Zamani, P.; Jamialahmadi, T.; Sahebkar, A. Long noncoding RNAs in nonalcoholic fatty liver disease and liver fibrosis: state-of-the-art and perspectives in diagnosis and treatment. Drug Discov. Today, 2020, 25(7), 1277-1286.
[http://dx.doi.org/10.1016/j.drudis.2020.05.009] [PMID: 32439605]
[7]
Mahmoudi, A.; Butler, A.E.; Jamialahmadi, T.; Sahebkar, A. The role of exosomal miRNA in nonalcoholic fatty liver disease. J. Cell. Physiol., 2022, 237(4), 2078-2094.
[http://dx.doi.org/10.1002/jcp.30699] [PMID: 35137416]
[8]
Mahjoubin-Tehran, M.; De Vincentis, A.; Mikhailidis, D.P.; Atkin, S.L.; Mantzoros, C.S.; Jamialahmadi, T.; Sahebkar, A. Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis. Mol. Metab., 2021, 50, 101049.
[http://dx.doi.org/10.1016/j.molmet.2020.101049] [PMID: 32673798]
[9]
Ranjbar, G.; Mikhailidis, D.P.; Sahebkar, A. Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box! Metabolism, 2019, 101, 154001.
[http://dx.doi.org/10.1016/j.metabol.2019.154001] [PMID: 31672448]
[10]
Mahmoudi, A.; Jamialahmadi, T.; Johnston, T.P.; Sahebkar, A. Impact of fenofibrate on NAFLD/NASH: A genetic perspective. Drug Discov. Today, 2022, 27(8), 2363-2372.
[http://dx.doi.org/10.1016/j.drudis.2022.05.007] [PMID: 35569762]
[11]
Moosavian, S.A.; Sathyapalan, T.; Jamialahmadi, T.; Sahebkar, A. The emerging role of nanomedicine in the management of nonalcoholic fatty liver disease: A state-of-the-art review. Bioinorg. Chem. Appl., 2021, 2021, 1-13.
[http://dx.doi.org/10.1155/2021/4041415] [PMID: 34659388]
[12]
Xu, X.; Poulsen, K.L.; Wu, L.; Liu, S.; Miyata, T.; Song, Q.; Wei, Q.; Zhao, C.; Lin, C.; Yang, J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct. Target. Ther., 2022, 7(1), 287.
[http://dx.doi.org/10.1038/s41392-022-01119-3] [PMID: 35963848]
[13]
Mantovani, A.; Dalbeni, A. Treatments for NAFLD: State of Art. Int. J. Mol. Sci., 2021, 26(22), 2350.
[14]
Wei, T.; Hao, W.; Tang, L.; Wu, H.; Huang, S.; Yang, Y.; Qian, N.; Liu, J.; Yang, W.; Duan, X. Comprehensive RNA-Seq analysis of potential therapeutic targets of Gan– dou–fu–mu decoction for treatment of wilson disease using a toxic milk mouse model. Front. Pharmacol., 2021, 12, 622268.
[http://dx.doi.org/10.3389/fphar.2021.622268] [PMID: 33935715]
[15]
Patel, K.; Sebastiani, G. Limitations of non-invasive tests for assessment of liver fibrosis. JHEP Reports, 2020, 2(2), 100067.
[http://dx.doi.org/10.1016/j.jhepr.2020.100067] [PMID: 32118201]
[16]
Wong, V.W.S.; Adams, L.A.; de Lédinghen, V.; Wong, G.L.H.; Sookoian, S. Noninvasive biomarkers in NAFLD and NASH - current progress and future promise. Nat. Rev. Gastroenterol. Hepatol., 2018, 15(8), 461-478.
[http://dx.doi.org/10.1038/s41575-018-0014-9] [PMID: 29844588]
[17]
Bolón-Canedo, V.; Alonso-Betanzos, A.; López-de-Ullibarri, I.; Cao, R. Challenges and future trends for microarray analysis. Methods Mol. Biol., 2019, 1986, 283-293.
[http://dx.doi.org/10.1007/978-1-4939-9442-7_14] [PMID: 31115895]
[18]
Churko, J.M.; Mantalas, G.L.; Snyder, M.P.; Wu, J.C. Overview of high throughput sequencing technologies to elucidate molecular pathways in cardiovascular diseases. Circ. Res., 2013, 112(12), 1613-1623.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.300939] [PMID: 23743227]
[19]
Nishimura, A.; Matsumoto, N. [Genomic microarray analysis of human diseases]. Jpn. J. Clin. Med., 2010, 68(S8), 235-241.
[PMID: 20976902]
[20]
Wang, S.; Cheng, Q. Microarray analysis in drug discovery and clinical applications. Methods Mol. Biol., 2006, 316, 49-65.
[http://dx.doi.org/10.1385/1-59259-964-8:49] [PMID: 16671400]
[21]
Clough, E.; Barrett, T. The gene expression omnibus database. Methods Mol. Biol., 2016, 1418, 93-110.
[http://dx.doi.org/10.1007/978-1-4939-3578-9_5] [PMID: 27008011]
[22]
Athanasios, A.; Charalampos, V.; Vasileios, T.; Ashraf, G. Protein-protein interaction (PPI) network: Recent advances in drug discovery. Curr. Drug Metab., 2017, 18(1), 5-10.
[http://dx.doi.org/10.2174/138920021801170119204832] [PMID: 28889796]
[23]
Mahmoudi, A.; Butler, A.E.; Majeed, M.; Banach, M.; Sahebkar, A. Investigation of the effect of curcumin on protein targets in nafld using bioinformatic analysis. Nutrients, 2022, 14(7), 1331.
[http://dx.doi.org/10.3390/nu14071331] [PMID: 35405942]
[24]
Mahmoudi, A.; Heydari, S.; Markina, Y.V.; Barreto, G.E.; Sahebkar, A. Role of statins in regulating molecular pathways following traumatic brain injury: A system pharmacology study. Biomed. Pharmacother., 2022, 153, 113304.
[http://dx.doi.org/10.1016/j.biopha.2022.113304] [PMID: 35724514]
[25]
Mahmoudi, A.; Butler, A.E.; Jamialahmadi, T.; Sahebkar, A. Target deconvolution of fenofibrate in nonalcoholic fatty liver disease using bioinformatics analysis. BioMed Res. Int., 2021, 2021, 1-14.
[http://dx.doi.org/10.1155/2021/3654660] [PMID: 34988225]
[26]
Liu, J.; Lin, B.; Chen, Z.; Deng, M.; Wang, Y.; Wang, J.; Chen, L.; Zhang, Z.; Xiao, X.; Chen, C.; Song, Y. Identification of key pathways and genes in nonalcoholic fatty liver disease using bioinformatics analysis. Arch. Med. Sci., 2020, 16(2), 374-385.
[http://dx.doi.org/10.5114/aoms.2020.93343] [PMID: 32190149]
[27]
Cotter, T.G.; Rinella, M. Nonalcoholic fatty liver disease 2020: The state of the disease. Gastroenterology, 2020, 158(7), 1851-1864.
[http://dx.doi.org/10.1053/j.gastro.2020.01.052] [PMID: 32061595]
[28]
Byrne, C.D.; Targher, G. NAFLD: A multisystem disease. J. Hepatol., 2015, 62(S1), S47-S64.
[http://dx.doi.org/10.1016/j.jhep.2014.12.012] [PMID: 25920090]
[29]
Liu, L.; Liu, C.; Zhao, M.; Zhang, Q.; Lu, Y.; Liu, P.; Yang, H.; Yang, J.; Chen, X.; Yao, Y. The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model. PLoS One, 2020, 15(12), e0243911.
[http://dx.doi.org/10.1371/journal.pone.0243911] [PMID: 33326461]
[30]
Ying, L.; Yan, F.; Zhao, Y.; Gao, H.; Williams, B.R.G.; Hu, Y.; Li, X.; Tian, R.; Xu, P.; Wang, Y. (-)-Epigallocatechin-3-gallate and atorvastatin treatment down-regulates liver fibrosis-related genes in non-alcoholic fatty liver disease. Clin. Exp. Pharmacol. Physiol., 2017, 44(12), 1180-1191.
[http://dx.doi.org/10.1111/1440-1681.12844] [PMID: 28815679]
[31]
Asadipooya, K.; Lankarani, K.B.; Raj, R.; Kalantarhormozi, M. RAGE is a potential cause of onset and progression of nonalcoholic fatty liver disease. Int. J. Endocrinol., 2019, 2019, 1-11.
[http://dx.doi.org/10.1155/2019/2151302] [PMID: 31641351]
[32]
Mahmoudi, A.; Atkin, S.L.; Nikiforov, N.G.; Sahebkar, A. Therapeutic role of curcumin in diabetes: An analysis based on bioinformatic findings. Nutrients, 2022, 14(15), 3244.
[http://dx.doi.org/10.3390/nu14153244] [PMID: 35956419]
[33]
Hu, Q.; Wei, S.; Wen, J.; Zhang, W.; Jiang, Y.; Qu, C.; Xiang, J.; Zhao, Y.; Peng, X.; Ma, X. Network pharmacology reveals the multiple mechanisms of Xiaochaihu decoction in the treatment of non-alcoholic fatty liver disease. BioData Min., 2020, 13(1), 11.
[http://dx.doi.org/10.1186/s13040-020-00224-9] [PMID: 32863886]
[34]
Zhang, M.; Yuan, Y.; Zhou, W.; Qin, Y.; Xu, K.; Men, J.; Lin, M. Network pharmacology analysis of Chaihu Lizhong Tang treating non-alcoholic fatty liver disease. Comput. Biol. Chem., 2020, 86, 107248.
[http://dx.doi.org/10.1016/j.compbiolchem.2020.107248] [PMID: 32208163]
[35]
Polo, M.L.; Riggio, M.; May, M.; Rodríguez, M.J.; Perrone, M.C.; Stallings-Mann, M.; Kaen, D.; Frost, M.; Goetz, M.; Boughey, J.; Lanari, C.; Radisky, D.; Novaro, V. Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression. Oncotarget, 2015, 6(26), 22081-22097.
[http://dx.doi.org/10.18632/oncotarget.4203] [PMID: 26098779]
[36]
Xia, P.; Xu, X.Y. PI3K/Akt/mTOR signaling pathway in cancer stem cells: From basic research to clinical application. Am. J. Cancer Res., 2015, 5(5), 1602-1609.
[PMID: 26175931]
[37]
Ersahin, T.; Tuncbag, N.; Cetin-Atalay, R. The PI3K/AKT/mTOR interactive pathway. Mol. Biosyst., 2015, 11(7), 1946-1954.
[http://dx.doi.org/10.1039/C5MB00101C] [PMID: 25924008]
[38]
Wang, R.; Song, F.; Li, S.; Wu, B.; Gu, Y.; Yuan, Y. Salvianolic acid A attenuates CCl4-induced liver fibrosis by regulating the PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways. Drug Des. Devel. Ther., 2019, 13, 1889-1900.
[http://dx.doi.org/10.2147/DDDT.S194787] [PMID: 31213776]
[39]
Ackers, I.; Malgor, R. Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases. Diab. Vasc. Dis. Res., 2018, 15(1), 3-13.
[http://dx.doi.org/10.1177/1479164117738442] [PMID: 29113510]
[40]
Tian, Y.; Mok, M.; Yang, P.; Cheng, A. Epigenetic activation of Wnt/β-catenin signaling in NAFLD-associated hepatocarcinogenesis. Cancers, 2016, 8(8), 76.
[http://dx.doi.org/10.3390/cancers8080076] [PMID: 27556491]
[41]
Wang, X-M.; Wang, X-Y.; Huang, Y-M.; Chen, X.; Lü, M-H.; Shi, L.; Li, C.P. Role and mechanisms of action of microRNA-21 as regards the regulation of the WNT/β- catenin signaling pathway in the pathogenesis of non-alcoholic fatty liver disease. Int. J. Mol. Med., 2019, 44(6), 2201-2212.
[http://dx.doi.org/10.3892/ijmm.2019.4375] [PMID: 31638173]
[42]
Wang, S.; Song, K.; Srivastava, R.; Dong, C.; Go, G.W.; Li, N.; Iwakiri, Y.; Mani, A. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. FASEB J., 2015, 29(8), 3436-3445.
[http://dx.doi.org/10.1096/fj.15-271171] [PMID: 25917329]
[43]
Luo, Z.Y.; Song, Q.; Xiong, X.P.; Abdulai, M.; Liu, H.H.; Li, L.; Xu, H.Y.; Hu, S.Q.; Han, C.C. The pi3k/akt/mtor signaling pathway regulates lipid metabolism mediated by endoplasmic reticulum stress in goose primary hepatocytes. Eur. Polit. Sci., 2021, 85, 1-15.
[44]
Liu, B.; Deng, X.; Jiang, Q.; Li, G.; Zhang, J.; Zhang, N.; Xin, S.; Xu, K. Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages. Biomed. Pharmacother., 2020, 125, 109895.
[http://dx.doi.org/10.1016/j.biopha.2020.109895] [PMID: 32000066]
[45]
Fan, Y.; He, Z.; Wang, W.; Li, J.; Hu, A.; Li, L.; Yan, L.; Li, Z.; Yin, Q. Tangganjian decoction ameliorates type 2 diabetes mellitus and nonalcoholic fatty liver disease in rats by activating the IRS/PI3K/AKT signaling pathway. Biomed. Pharmacother., 2018, 106, 733-737.
[http://dx.doi.org/10.1016/j.biopha.2018.06.089] [PMID: 29990865]
[46]
Hohwieler, M.; Perkhofer, L.; Liebau, S.; Seufferlein, T.; Müller, M.; Illing, A.; Kleger, A. Stem cell-derived organoids to model gastrointestinal facets of cystic fibrosis. United European Gastroenterol. J., 2017, 5(5), 609-624.
[http://dx.doi.org/10.1177/2050640616670565] [PMID: 28815024]
[47]
Mallea, J.; Bolan, C.; Cortese, C.; Harnois, D. Cystic fibrosis–associated liver disease in lung transplant recipients. Liver Transpl., 2019, 25(8), 1265-1275.
[http://dx.doi.org/10.1002/lt.25496] [PMID: 31102574]
[48]
Martin, C.R.; Zaman, M.M.; Ketwaroo, G.A.; Bhutta, A.Q.; Coronel, E.; Popov, Y.; Schuppan, D.; Freedman, S.D. CFTR dysfunction predisposes to fibrotic liver disease in a murine model. Am. J. Physiol. Gastrointest. Liver Physiol., 2012, 303(4), G474-G481.
[http://dx.doi.org/10.1152/ajpgi.00055.2012] [PMID: 22679000]
[49]
Ricard-Blum, S. The collagen family. Cold Spring Harb. Perspect. Biol., 2011, 3(1), a004978.
[http://dx.doi.org/10.1101/cshperspect.a004978] [PMID: 21421911]
[50]
Escutia-Gutiérrez, R.; Rodríguez-Sanabria, J.S.; Monraz-Méndez, C.A.; García-Bañuelos, J.; Santos-García, A.; Sandoval-Rodríguez, A.; Armendáriz-Borunda, J. Pirfenidone modifies hepatic miRNAs expression in a model of MAFLD/NASH. Sci. Rep., 2021, 11(1), 11709.
[http://dx.doi.org/10.1038/s41598-021-91187-2] [PMID: 34083664]
[51]
Sámano-Hernández, L.; Fierro, R.; Marchal, A.; Guéant, J.L.; González-Márquez, H.; Guéant-Rodríguez, R.M. Beneficial and deleterious effects of sitagliptin on a methionine/choline-deficient diet-induced steatohepatitis in rats. Biochimie, 2021, 181, 240-248.
[http://dx.doi.org/10.1016/j.biochi.2020.12.004] [PMID: 33333172]
[52]
Fan, Y.; Fang, X.; Tajima, A.; Geng, X.; Ranganathan, S.; Dong, H.; Trucco, M.; Sperling, M.A. Evolution of hepatic steatosis to fibrosis and adenoma formation in liver-specific growth hormone receptor knockout mice. Front. Endocrinol., 2014, 5, 218.
[http://dx.doi.org/10.3389/fendo.2014.00218] [PMID: 25566190]
[53]
Islam, S.; Watanabe, H. Versican: A dynamic regulator of the extracellular matrix. J. Histochem. Cytochem., 2020, 68(11), 763-775.
[http://dx.doi.org/10.1369/0022155420953922] [PMID: 33131383]
[54]
Bukong, T.N.; Maurice, S.B.; Chahal, B.; Schaeffer, D.F.; Winwood, P.J. Versican: A novel modulator of hepatic fibrosis. Lab. Invest., 2016, 96(3), 361-374.
[http://dx.doi.org/10.1038/labinvest.2015.152] [PMID: 26752747]
[55]
Wight, T.N.; Kang, I.; Merrilees, M.J. Versican and the control of inflammation. Matrix Biol., 2014, 35, 152-161.
[http://dx.doi.org/10.1016/j.matbio.2014.01.015] [PMID: 24513039]
[56]
Kim, S.; Takahashi, H.; Lin, W.W.; Descargues, P.; Grivennikov, S.; Kim, Y.; Luo, J.L.; Karin, M. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature, 2009, 457(7225), 102-106.
[http://dx.doi.org/10.1038/nature07623] [PMID: 19122641]
[57]
Kesteloot, F.; Desmoulière, A.; Leclercq, I.; Thiry, M.; Arrese, J.E.; Prockop, D.J.; Lapière, C.M.; Nusgens, B.V.; Colige, A. ADAM metallopeptidase with thrombospondin type 1 motif 2 inactivation reduces the extent and stability of carbon tetrachloride-induced hepatic fibrosis in mice. Hepatology, 2007, 46(5), 1620-1631.
[http://dx.doi.org/10.1002/hep.21868] [PMID: 17929299]
[58]
Bauters, D.; Spincemaille, P.; Geys, L.; Cassiman, D.; Vermeersch, P.; Bedossa, P.; Scroyen, I.; Lijnen, H.R. ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity. Liver Int., 2016, 36(12), 1848-1859.
[http://dx.doi.org/10.1111/liv.13181] [PMID: 27254774]
[59]
Ramnath, D.; Irvine, K.M.; Lukowski, S.W.; Horsfall, L.U.; Loh, Z.; Clouston, A.D.; Patel, P.J.; Fagan, K.J.; Iyer, A.; Lampe, G.; Stow, J.L.; Schroder, K.; Fairlie, D.P.; Powell, J.E.; Powell, E.E.; Sweet, M.J. Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes. JCI Insight, 2018, 3(14), e120274.
[http://dx.doi.org/10.1172/jci.insight.120274] [PMID: 30046009]
[60]
Sadler, J.E. Biochemistry and genetics of von Willebrand factor. Annu. Rev. Biochem., 1998, 67(1), 395-424.
[http://dx.doi.org/10.1146/annurev.biochem.67.1.395] [PMID: 9759493]
[61]
Groeneveld, D.J.; Poole, L.G.; Luyendyk, J.P. Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy? J. Thromb. Haemost., 2021, 19(6), 1390-1408.
[http://dx.doi.org/10.1111/jth.15312] [PMID: 33774926]
[62]
Rosito, G.; D’Agostino, R.; Massaro, J.; Lipinska, I.; Mittleman, M.; Sutherland, P.; Wilson, P.; Levy, D.; Muller, J.; Tofler, G. Association between obesity and a prothrombotic state: The Framingham Offspring Study. Thromb. Haemost., 2004, 91(4), 683-689.
[http://dx.doi.org/10.1160/TH03-01-0014] [PMID: 15045128]
[63]
Bilgir, O.; Bilgir, F.; Bozkaya, G.; Calan, M. Changes in the levels of endothelium-derived coagulation parameters in nonalcoholic fatty liver disease. Blood Coagul. Fibrinolysis, 2014, 25(2), 151-155.
[http://dx.doi.org/10.1097/MBC.0000000000000009] [PMID: 24317388]
[64]
Danoy, M.; Jellali, R.; Tauran, Y.; Bruce, J.; Leduc, M.; Gilard, F.; Gakière, B.; Scheidecker, B.; Kido, T.; Miyajima, A.; Soncin, F.; Sakai, Y.; Leclerc, E. Characterization of the proteome and metabolome of human liver sinusoidal endothelial-like cells derived from induced pluripotent stem cells. Differentiation, 2021, 120, 28-35.
[http://dx.doi.org/10.1016/j.diff.2021.06.001] [PMID: 34229994]
[65]
Yang, J.; Lu, Y.; Lou, X.; Wang, J.; Yu, H.; Bao, Z.; Wang, H. Von willebrand factor deficiency improves hepatic steatosis, insulin resistance, and inflammation in mice fed high-fat diet. Obesity, 2020, 28(4), 756-764.
[http://dx.doi.org/10.1002/oby.22744] [PMID: 32144880]
[66]
Menggensilimu; Yuan, H.; Zhao, C.; Bao, X.; Wang, H.; Liang, J.; Yan, Y.; Zhang, C.; Jin, R.; Ma, L.; Zhang, J.; Su, X.; Ma, Y. Anti-liver fibrosis effect of total flavonoids from Scabiosa comosa Fisch. ex Roem. et Schult. on liver fibrosis in rat models and its proteomics analysis. Ann. Palliat. Med., 2020, 9(2), 272-285.
[http://dx.doi.org/10.21037/apm.2020.02.29] [PMID: 32233617]
[67]
Fisher, L.W.; Torchia, D.A.; Fohr, B.; Young, M.F.; Fedarko, N.S. Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochem. Biophys. Res. Commun., 2001, 280(2), 460-465.
[http://dx.doi.org/10.1006/bbrc.2000.4146] [PMID: 11162539]
[68]
Sahai, A.; Malladi, P.; Melin-Aldana, H.; Green, R.M.; Whitington, P.F. Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, 287(1), G264-G273.
[http://dx.doi.org/10.1152/ajpgi.00002.2004] [PMID: 15044174]
[69]
Banerjee, A.; Rose, R.; Johnson, G.A.; Burghardt, R.C.; Ramaiah, S.K. The influence of estrogen on hepatobiliary osteopontin (SPP1) expression in a female rodent model of alcoholic steatohepatitis. Toxicol. Pathol., 2009, 37(4), 492-501.
[http://dx.doi.org/10.1177/0192623309335633] [PMID: 19387089]
[70]
Sweetwyne, M.T.; Murphy-Ullrich, J.E. Thrombospondin1 in tissue repair and fibrosis: TGF-β-dependent and independent mechanisms. Matrix Biol., 2012, 31(3), 178-186.
[http://dx.doi.org/10.1016/j.matbio.2012.01.006] [PMID: 22266026]
[71]
Adams, J.C.; Lawler, J. The Thrombospondins. Cold Spring Harb. Perspect. Biol., 2011, 3(10), a009712.
[http://dx.doi.org/10.1101/cshperspect.a009712] [PMID: 21875984]
[72]
Maimaitiyiming, H.; Clemons, K.; Zhou, Q.; Norman, H.; Wang, S. Thrombospondin1 deficiency attenuates obesity-associated microvascular complications in ApoE-/- mice. PLoS One, 2015, 10(3), e0121403.
[http://dx.doi.org/10.1371/journal.pone.0121403] [PMID: 25803585]
[73]
Wang, S.; Lincoln, T.M.; Murphy-Ullrich, J.E. Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-β activity in vascular smooth muscle cells. Am. J. Physiol. Cell Physiol., 2010, 298(5), C1188-C1197.
[http://dx.doi.org/10.1152/ajpcell.00330.2009] [PMID: 20164378]
[74]
Lopez-Dee, Z.; Pidcock, K.; Gutierrez, L.S. Thrombospondin-1: Multiple paths to inflammation. Mediators Inflamm., 2011, 2011, 1-10.
[http://dx.doi.org/10.1155/2011/296069] [PMID: 21765615]
[75]
Li, Y.; Turpin, C.P.; Wang, S. Role of thrombospondin 1 in liver diseases. Hepatol. Res., 2017, 47(2), 186-193.
[http://dx.doi.org/10.1111/hepr.12787] [PMID: 27492250]
[76]
Min-DeBartolo, J.; Schlerman, F.; Akare, S.; Wang, J.; McMahon, J.; Zhan, Y.; Syed, J.; He, W.; Zhang, B.; Martinez, R.V. Thrombospondin-I is a critical modulator in non-alcoholic steatohepatitis (NASH). PLoS One, 2019, 14(12), e0226854.
[http://dx.doi.org/10.1371/journal.pone.0226854] [PMID: 31891606]
[77]
Li, Y.; Qi, X.; Tong, X.; Wang, S. Thrombospondin 1 activates the macrophage Toll-like receptor 4 pathway. Cell. Mol. Immunol., 2013, 10(6), 506-512.
[http://dx.doi.org/10.1038/cmi.2013.32] [PMID: 23954950]
[78]
Gwag, T.; Reddy Mooli, R.G.; Li, D.; Lee, S.; Lee, E.Y.; Wang, S. Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease. JHEP Reports, 2021, 3(1), 100193.
[http://dx.doi.org/10.1016/j.jhepr.2020.100193] [PMID: 33294831]
[79]
Song, Y.; Gao, L. Thrombospondin1 as a potential therapeutic target for human nonalcoholic fatty liver disease. EBioMedicine, 2020, 58, 102888.
[http://dx.doi.org/10.1016/j.ebiom.2020.102888] [PMID: 32697967]
[80]
Kimura, T.; Tanaka, N.; Fujimori, N.; Yamazaki, T.; Katsuyama, T.; Iwashita, Y.; Pham, J.; Joshita, S.; Pydi, S.P.; Umemura, T. Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD. Liver Int., 2021, 41(3), 505-514.
[http://dx.doi.org/10.1111/liv.14776] [PMID: 33386676]
[81]
Wolff, G.; Taranko, A.E.; Meln, I.; Weinmann, J.; Sijmonsma, T.; Lerch, S.; Heide, D.; Billeter, A.T.; Tews, D.; Krunic, D.; Fischer-Posovszky, P.; Müller-Stich, B.P.; Herzig, S.; Grimm, D.; Heikenwälder, M.; Kao, W.W.; Vegiopoulos, A. Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis. Mol. Metab., 2019, 19, 97-106.
[http://dx.doi.org/10.1016/j.molmet.2018.10.007] [PMID: 30409703]
[82]
Charlton, M.; Viker, K.; Krishnan, A.; Sanderson, S.; Veldt, B.; Kaalsbeek, A.J.; Kendrick, M.; Thompson, G.; Que, F.; Swain, J.; Sarr, M. Differential expression of lumican and fatty acid binding protein-1: New insights into the histologic spectrum of nonalcoholic fatty liver disease. Hepatology, 2009, 49(4), 1375-1384.
[http://dx.doi.org/10.1002/hep.22927] [PMID: 19330863]
[83]
Krishnan, A.; Li, X.; Kao, W.Y.; Viker, K.; Butters, K.; Masuoka, H.; Knudsen, B.; Gores, G.; Charlton, M. Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis. Lab. Invest., 2012, 92(12), 1712-1725.
[http://dx.doi.org/10.1038/labinvest.2012.121] [PMID: 23007134]
[84]
Decaris, M.L.; Li, K.W.; Emson, C.L.; Gatmaitan, M.; Liu, S.; Wang, Y.; Nyangau, E.; Colangelo, M.; Angel, T.E.; Beysen, C.; Cui, J.; Hernandez, C.; Lazaro, L.; Brenner, D.A.; Turner, S.M.; Hellerstein, M.K.; Loomba, R. Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood. Hepatology, 2017, 65(1), 78-88.
[http://dx.doi.org/10.1002/hep.28860] [PMID: 27706836]
[85]
Chang, Y.; He, J.; Xiang, X.; Li, H. LUM is the hub gene of advanced fibrosis in nonalcoholic fatty liver disease patients. Clin. Res. Hepatol. Gastroenterol., 2021, 45(1), 101435.
[http://dx.doi.org/10.1016/j.clinre.2020.04.006] [PMID: 32386798]
[86]
Karamfilova, V.; Gateva, A.; Assyov, Y.; Nedeva, I.; Velikova, T.; Cherkezov, N.; Mateva, L.; Kamenov, Z. Lumican in obese patients with nonalcoholic fatty liver disease with or without prediabetes. Metab. Syndr. Relat. Disord., 2020, 18(9), 443-448.
[http://dx.doi.org/10.1089/met.2020.0001] [PMID: 32780624]
[87]
Ciupińska-Kajor, M.; Hartleb, M.; Kajor, M.; Kukla, M.; Wyleżoł, M.; Lange, D.; Liszka, Ł. Hepatic angiogenesis and fibrosis are common features in morbidly obese patients. Hepatol. Int., 2013, 7(1), 233-240.
[http://dx.doi.org/10.1007/s12072-011-9320-9] [PMID: 23519653]
[88]
Suzawa, K.; Kobayashi, M.; Sakai, Y.; Hoshino, H.; Watanabe, M.; Harada, O.; Ohtani, H.; Fukuda, M.; Nakayama, J. Preferential induction of peripheral lymph node addressin on high endothelial venule-like vessels in the active phase of ulcerative colitis. Am. J. Gastroenterol., 2007, 102(7), 1499-1509.
[http://dx.doi.org/10.1111/j.1572-0241.2007.01189.x] [PMID: 17459027]
[89]
Strilić, B.; Kučera, T.; Eglinger, J.; Hughes, M.R.; McNagny, K.M.; Tsukita, S.; Dejana, E.; Ferrara, N.; Lammert, E. The molecular basis of vascular lumen formation in the developing mouse aorta. Dev. Cell, 2009, 17(4), 505-515.
[http://dx.doi.org/10.1016/j.devcel.2009.08.011] [PMID: 19853564]
[90]
Shi, J.F.; Xu, S.X.; He, P.; Xi, Z.H. Expression of carcinoembryonic antigen-related cell adhesion molecule 1(CEACAM1) and its correlation with angiogenesis in gastric cancer. Pathol. Res. Pract., 2014, 210(8), 473-476.
[http://dx.doi.org/10.1016/j.prp.2014.03.014] [PMID: 24846314]
[91]
Kukla, M.; Gabriel, A.; Sabat, D.; Liszka, Ł.; Wilk, M.; Petelenz, M.; Musialik, J.; Dzindziora-Frelich, I. Association between liver steatosis and angiogenesis in chronic hepatitis C. Pol. J. Pathol., 2010, 61(3), 154-160.
[PMID: 21225498]
[92]
Tsuji, N.; Ishiguro, S.; Sasaki, Y.; Kudo, M. CD34 expression in noncancerous liver tissue predicts multicentric recurrence of hepatocellular carcinoma. Dig. Dis., 2013, 31(5-6), 467-471.
[http://dx.doi.org/10.1159/000355246] [PMID: 24281022]
[93]
Cui, D.J.; Wu, Y.; Wen, D.H. CD34, PCNA and CK19 expressions in AFP-hepatocellular carcinoma. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(16), 5200-5205.
[PMID: 30178842]
[94]
Yan, W.W.; Huang, A.; Li, Y.G.; Wang, S.S.; Dai, G.H. [Expressions of CD34 and CD117 in human hepatocellular carcinomas and the clinical significance]. Zhonghua Gan Zang Bing Za Zhi, 2011, 19(8), 588-593.
[PMID: 22152315]
[95]
Zhang, Q.; Chen, X.; Zhou, J.; Zhang, L.; Zhao, Q.; Chen, G.; Xu, J.; Feng, Q.; Chen, Z. CD147, MMP-2, MMP-9 and MVD-CD34 are significant predictors of recurrence after liver transplantation in hepatocellular carcinoma patients. Cancer Biol. Ther., 2006, 5(7), 808-814.
[http://dx.doi.org/10.4161/cbt.5.7.2754] [PMID: 16775432]
[96]
Choi, W.T.; Kakar, S. Immunohistochemistry in the diagnosis of hepatocellular carcinoma. Gastroenterol. Clin. North Am., 2017, 46(2), 311-325.
[http://dx.doi.org/10.1016/j.gtc.2017.01.006] [PMID: 28506367]
[97]
Li, Y.; Song, D.; Mao, L.; Abraham, D.M.; Bursac, N. Lack of Thy1 defines a pathogenic fraction of cardiac fibroblasts in heart failure. Biomaterials, 2020, 236, 119824.
[http://dx.doi.org/10.1016/j.biomaterials.2020.119824] [PMID: 32028169]
[98]
Dudas, J.; Mansuroglu, T.; Batusic, D.; Saile, B.; Ramadori, G. Thy-1 is an in vivo and in vitro marker of liver myofibroblasts. Cell Tissue Res., 2007, 329(3), 503-514.
[http://dx.doi.org/10.1007/s00441-007-0437-z] [PMID: 17576600]
[99]
Kon, J.; Ichinohe, N.; Ooe, H.; Chen, Q.; Sasaki, K.; Mitaka, T. Thy1-positive cells have bipotential ability to differentiate into hepatocytes and biliary epithelial cells in galactosamine-induced rat liver regeneration. Am. J. Pathol., 2009, 175(6), 2362-2371.
[http://dx.doi.org/10.2353/ajpath.2009.080338] [PMID: 19893024]
[100]
Zheng, J.; Wu, H.; Zhang, Z.; Yao, S. Dynamic co-expression modular network analysis in nonalcoholic fatty liver disease. Hereditas, 2021, 158(1), 31.
[http://dx.doi.org/10.1186/s41065-021-00196-8] [PMID: 34419146]
[101]
Pepper, S.D.; Saunders, E.K.; Edwards, L.E.; Wilson, C.L.; Miller, C.J. The utility of MAS5 expression summary and detection call algorithms. BMC Bioinformatics, 2007, 8(1), 273.
[http://dx.doi.org/10.1186/1471-2105-8-273] [PMID: 17663764]
[102]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[103]
Jacomy, M.; Venturini, T.; Heymann, S.; Bastian, M. ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software. PLoS One, 2014, 9(6), e98679.
[http://dx.doi.org/10.1371/journal.pone.0098679] [PMID: 24914678]

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