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The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.<\/jats:p>","DOI":"10.3390\/ijms23095230","type":"journal-article","created":{"date-parts":[[2022,5,8]],"date-time":"2022-05-08T08:04:21Z","timestamp":1651997061000},"page":"5230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Downregulation of miR-122-5p Activates Glycolysis via PKM2 in Kupffer Cells of Rat and Mouse Models of Non-Alcoholic Steatohepatitis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4897-5707","authenticated-orcid":false,"given":"Yosuke","family":"Inomata","sequence":"first","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Won","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Translational Research Program, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1892-9005","authenticated-orcid":false,"given":"Nobuhiko","family":"Sugito","sequence":"additional","affiliation":[{"name":"United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitoshi","family":"Hirokawa","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Woong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Akao","sequence":"additional","affiliation":[{"name":"United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Takai","sequence":"additional","affiliation":[{"name":"Department of Innovative Medicine, Graduate School of Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-3787","authenticated-orcid":false,"given":"Kwang-Pyo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Uchiyama","sequence":"additional","affiliation":[{"name":"Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score and the Histopathologic Diagnosis in NAFLD: Distinct Clinicopathologic Meanings","volume":"53","author":"Brunt","year":"2011","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/s41575-018-0014-9","article-title":"Noninvasive Biomarkers in NAFLD and NASH\u2014Current Progress and Future Promise","volume":"15","author":"Wong","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S104","DOI":"10.1016\/j.jhep.2008.01.009","article-title":"Non-alcoholic Fatty Liver Disease: The Mist Gradually Clears","volume":"48","author":"Day","year":"2008","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/j.1440-1746.2008.05640.x","article-title":"Clinical Features and Outcomes of Cirrhosis Due to Non-alcoholic Steatohepatitis Compared with Cirrhosis Caused by Chronic Hepatitis C","volume":"24","author":"Yatsuji","year":"2009","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the Origin of Cancer Cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nature06734","article-title":"The M2 Splice Isoform of Pyruvate Kinase Is Important for Cancer Metabolism and Tumour Growth","volume":"452","author":"Christofk","year":"2008","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.canlet.2015.03.026","article-title":"MicroRNA-124 Inhibits Cancer Cell Growth through PTB1\/PKM1\/PKM2 Feedback Cascade in Colorectal Cancer","volume":"363","author":"Taniguchi","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1111\/cas.13091","article-title":"MiR-133b Inhibits Growth of Human Gastric Cancer Cells by Silencing Pyruvate Kinase Muscle-Splicer Polypyrimidine Tract-Binding Protein 1","volume":"107","author":"Sugiyama","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Takai, T., Yoshikawa, Y., Inamoto, T., Minami, K., Taniguchi, K., Sugito, N., Kuranaga, Y., Shinohara, H., Kumazaki, M., and Tsujino, T. (2017). A Novel Combination RNAi toward Warburg Effect by Replacement with miR-145 and Silencing of PTBP1 Induces Apoptotic Cell Death in Bladder Cancer Cells. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18010179"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8647","DOI":"10.1038\/srep08647","article-title":"Organ-Specific PTB1-Associated microRNAs Determine Expression of Pyruvate Kinase Isoforms","volume":"5","author":"Taniguchi","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"18940","DOI":"10.18632\/oncotarget.8005","article-title":"PTBP1-Associated microRNA-1 and -133b Suppress the Warburg Effect in Colorectal Tumors","volume":"7","author":"Taniguchi","year":"2016","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4436","DOI":"10.1038\/ncomms5436","article-title":"PKM2 Regulates the Warburg Effect and Promotes HMGB1 Release in Sepsis","volume":"5","author":"Yang","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1084\/jem.20150900","article-title":"The Glycolytic Enzyme PKM2 Bridges Metabolic and Inflammatory Dysfunction in Coronary Artery Disease","volume":"213","author":"Shirai","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.cell.2009.01.002","article-title":"MicroRNAs: Target Recognition and Regulatory Functions","volume":"136","author":"Bartel","year":"2009","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S0960-9822(02)00809-6","article-title":"Identification of Tissue-Specific microRNAs from Mouse","volume":"12","author":"Rauhut","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"106","DOI":"10.4161\/rna.1.2.1066","article-title":"miR-122, a Mammalian Liver-Specific microRNA, is Processed from hcr mRNA and May Downregulate the High Affinity Cationic Amino Acid Transporter CAT-1","volume":"1","author":"Chang","year":"2004","journal-title":"RNA Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1002\/hep.22569","article-title":"Nonalcoholic Steatohepatitis Is Associated with Altered Hepatic microRNA Expression","volume":"48","author":"Cheung","year":"2008","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1002\/hep.25873","article-title":"Circulating microRNAs in Exosomes Indicate Hepatocyte Injury and Inflammation in Alcoholic, Drug-Induced, and Inflammatory Liver Diseases","volume":"56","author":"Bala","year":"2012","journal-title":"Hepatology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.jphs.2017.04.005","article-title":"Chymase Inhibitor Prevents the Development and Progression of Non-alcoholic Steatohepatitis in Rats Fed a High-Fat and High-Cholesterol Diet","volume":"134","author":"Miyaoka","year":"2017","journal-title":"J. Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1538\/expanim.17-0126","article-title":"A Novel Hamster Nonalcoholic Steatohepatitis Model Induced by a High-Fat and High-Cholesterol Diet","volume":"67","author":"Miyaoka","year":"2018","journal-title":"Exp. Anim."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s12199-011-0235-9","article-title":"Development of Novel Rat Model for High-Fat and High-Cholesterol Diet-Induced Steatohepatitis and Severe Fibrosis Progression in SHRSP5\/Dmcr","volume":"17","author":"Kitamori","year":"2012","journal-title":"Environ. Health Prev. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Taniguchi, K., Sugito, N., Shinohara, H., Kuranaga, Y., Inomata, Y., Komura, K., Uchiyama, K., and Akao, Y. (2018). Organ-Specific microRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1\/2 (PKM) Expression. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051276"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/0006-291X(68)90705-5","article-title":"Some Distinctive Properties of Pyruvate Kinase Purified from Rat Liver","volume":"30","author":"Susor","year":"1968","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/iep.12008","article-title":"An Improved Mouse Model That Rapidly Develops Fibrosis in Non-alcoholic Steatohepatitis","volume":"94","author":"Matsumoto","year":"2013","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s10620-014-3189-0","article-title":"Pyruvate Kinase M2 Regulates Apoptosis of Intestinal Epithelial Cells in Crohn\u2019s Disease","volume":"60","author":"Tang","year":"2015","journal-title":"Dig. Dis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cmet.2014.12.005","article-title":"Pyruvate Kinase M2 Regulates HIF-1\u03b1 Activity and IL-1\u03b2 Induction and is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages","volume":"21","author":"Curtis","year":"2015","journal-title":"Cell Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/iep.12240","article-title":"Hepatocellular Carcinoma in a Mouse Model Fed a Choline-Deficient, L-Amino Acid-Defined, High-Fat Diet","volume":"98","author":"Matsuo","year":"2017","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1002\/cphy.c120026","article-title":"Kupffer Cells in the Liver","volume":"3","author":"Dixon","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1111\/j.1478-3231.2006.01342.x","article-title":"Role of Kupffer Cells in Host Defense and Liver Disease","volume":"26","author":"Bilzer","year":"2006","journal-title":"Liver Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1097\/01.mog.0000182863.96421.47","article-title":"Role of Inflammation in Nonalcoholic Steatohepatitis","volume":"21","author":"Choi","year":"2005","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1002\/hep.22399","article-title":"Beyond Insulin Resistance: Innate Immunity in Nonalcoholic Steatohepatitis","volume":"48","author":"Maher","year":"2008","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"342","DOI":"10.4049\/jimmunol.175.1.342","article-title":"Macrophages Sequentially Change Their Functional Phenotype in Response to Changes in Microenvironmental Influences","volume":"175","author":"Stout","year":"2005","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/hep.26607","article-title":"M2 Kupffer Cells Promote M1 Kupffer Cell Apoptosis: A Protective Mechanism against Alcoholic and Nonalcoholic Fatty Liver Disease","volume":"59","author":"Wan","year":"2014","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nrgastro.2013.140","article-title":"Liver disease: Kupffer Cells Regulate the Progression of ALD and NAFLD","volume":"10","author":"Smith","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/cr.2015.68","article-title":"Metabolic Reprogramming in Macrophages and Dendritic Cells in Innate Immunity","volume":"25","author":"Kelly","year":"2015","journal-title":"Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.3389\/fimmu.2019.01462","article-title":"The Metabolic Signature of Macrophage Responses","volume":"10","author":"Viola","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 Paradigm of Macrophage Activation: Time for Reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"803037","DOI":"10.3389\/fimmu.2021.803037","article-title":"Macrophage Polarization and Its Role in Liver Disease","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.humpath.2008.08.011","article-title":"High Tumor-Infiltrating Macrophage Density Predicts Poor Prognosis in Patients with Primary Hepatocellular Carcinoma after Resection","volume":"40","author":"Ding","year":"2009","journal-title":"Hum. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00432-008-0469-0","article-title":"Tumor-Infiltrating Macrophages Can Predict Favorable Prognosis in Hepatocellular Carcinoma after Resection","volume":"135","author":"Li","year":"2009","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1158\/2159-8290.CD-15-1346","article-title":"Macrophage PI3K\u03b3 Drives Pancreatic Ductal Adenocarcinoma Progression","volume":"6","author":"Kaneda","year":"2016","journal-title":"Cancer. Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature19834","article-title":"PI3K\u03b3 is a Molecular Switch That Controls Immune Suppression","volume":"539","author":"Kaneda","year":"2016","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101634","DOI":"10.1016\/j.redox.2020.101634","article-title":"Annexin A5 Regulates Hepatic Macrophage Polarization via Directly Targeting PKM2 and Ameliorates NASH","volume":"36","author":"Xu","year":"2020","journal-title":"Redox. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"174750","DOI":"10.1016\/j.ejphar.2022.174750","article-title":"Dichloroacetate Reactivates Pyruvate-Supported Peroxide Removal by Liver Mitochondria and Prevents NAFLD Aggravation in NAD(P)+ Transhydrogenase-Null Mice Consuming a High-Fat Diet","volume":"917","author":"Navarro","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1021\/acsptsci.0c00208","article-title":"Pyruvate Dehydrogenase as a Therapeutic Target for Nonalcoholic Fatty Liver Disease","volume":"4","author":"Saed","year":"2021","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.molmet.2018.03.014","article-title":"Targeting Hepatic Pyruvate Dehydrogenase Kinases Restores Insulin Signaling and Mitigates ChREBP-Mediated Lipogenesis in Diet-Induced Obese Mice","volume":"12","author":"Wu","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Liu, A.M., Xu, Z., Shek, F.H., Wong, K.F., Lee, N.P., Poon, R.T., Chen, J., and Luk, J.M. (2014). miR-122 Targets Pyruvate Kinase M2 and Affects Metabolism of Hepatocellular Carcinoma. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086872"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.3892\/or.2015.4175","article-title":"MicroRNA-122 Affects Cell Aggressiveness and Apoptosis by Targeting PKM2 in Human Hepatocellular Carcinoma","volume":"34","author":"Xu","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/cas.14694","article-title":"PTBP1-Targeting microRNAs Regulate Cancer-Specific Energy Metabolism through the Modulation of PKM1\/M2 Splicing","volume":"112","author":"Taniguchi","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Nakamura, M., Kanda, T., Sasaki, R., Haga, Y., Jiang, X., Wu, S., Nakamoto, S., and Yokosuka, O. (2015). MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0144295"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"G1035","DOI":"10.1152\/ajpgi.00199.2004","article-title":"Obese and Diabetic db\/db Mice Develop Marked Liver Fibrosis in a Model of Nonalcoholic Steatohepatitis: Role of Short-Form Leptin Receptors and Osteopontin","volume":"287","author":"Sahai","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.hepres.2005.09.026","article-title":"Hepatocyte-Specific Pten-Deficient Mice as a Novel Model for Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma","volume":"33","author":"Watanabe","year":"2005","journal-title":"Hepatol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1478-3231.2006.01405.x","article-title":"Yo Jyo Hen Shi Ko, A Novel Chinese Herbal, Prevents Nonalcoholic Steatohepatitis in ob\/ob Mice Fed a High Fat or Methionine-Choline-Deficient Diet","volume":"27","author":"Sawada","year":"2007","journal-title":"Liver Int."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"C377","DOI":"10.1152\/ajpcell.1990.258.3.C377","article-title":"Regulation of Oxidative Phosphorylation in the Mammalian Cell","volume":"258","author":"Balaban","year":"1990","journal-title":"Am. J. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Li, Y., Ren, Q., Zhu, L., Li, Y., Li, J., Zhang, Y., Zheng, G., Han, T., Sun, S., and Feng, F. (2018). Involvement of Methylation of MicroRNA-122, -125b and -106b in Regulation of Cyclin G1, CAT-1 and STAT3 Target Genes in Isoniazid-Induced Liver Injury. BMC Pharmacol. Toxicol., 19.","DOI":"10.1186\/s40360-018-0201-x"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1038\/onc.2009.211","article-title":"Loss of miR-122 Expression in Liver Cancer Correlates with Suppression of the Hepatic Phenotype and Gain of Metastatic Properties","volume":"28","author":"Coulouarn","year":"2009","journal-title":"Oncogene"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1002\/hep.23818","article-title":"Liver-Enriched Transcription Factors Regulate microRNA-122 that Targets CUTL1 during Liver Development","volume":"52","author":"Xu","year":"2010","journal-title":"Hepatology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.jhep.2010.12.023","article-title":"Positive Regulation of Hepatic miR-122 Expression by HNF4\u03b1","volume":"55","author":"Li","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1500462","DOI":"10.1002\/pmic.201500462","article-title":"Proteomics of Hydrophobic Samples: Fast, Robust and Low-Cost Workflows for Clinical Approaches","volume":"17","author":"Pasing","year":"2017","journal-title":"Proteomics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1038\/s41596-018-0014-9","article-title":"High-Throughput and High-Sensitivity Phosphoproteomics with the EasyPhos Platform","volume":"13","author":"Humphrey","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e1800200","DOI":"10.1002\/pmic.201800200","article-title":"GASP and FASP are Complementary for LC-MS\/MS Proteomic Analysis of Drug-Metabolizing Enzymes and Transporters in Pig Liver","volume":"18","author":"Howard","year":"2018","journal-title":"Proteomics"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1021\/ac0262560","article-title":"Tandem Mass Tags: A Novel Quantification Strategy for Comparative Analysis of Complex Protein Mixtures by MS\/MS","volume":"75","author":"Thompson","year":"2003","journal-title":"Anal. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1074\/mcp.M700419-MCP200","article-title":"Postexperiment Monoisotopic Mass Filtering and Refinement (PE-MMR) of Tandem Mass Spectrometric Data Increases Accuracy of Peptide Identification in LC\/MS\/MS","volume":"7","author":"Shin","year":"2008","journal-title":"Mol. Cell. Proteom."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5354","DOI":"10.1021\/pr200611n","article-title":"Universal and Confident Phosphorylation Site Localization using phosphoRS","volume":"10","author":"Taus","year":"2011","journal-title":"J. Proteome Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and Integrative Analysis of Large Gene Lists using DAVID Bioinformatics Resources","volume":"4","author":"Sherman","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0006-8993(78)90035-5","article-title":"Input to Primate Motor Cortex from Posterior Parietal Cortex (area 5). I. Demonstration by Retrograde Transport","volume":"157","author":"Strick","year":"1978","journal-title":"Brain Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4542","DOI":"10.1021\/acs.molpharmaceut.9b00680","article-title":"\u03b1-aminoisobutyric acid-Containing Amphipathic Helical Peptide-cyclic RGD Conjugation as a Potential Drug Delivery System for microRNA Replacement Therapy in vitro","volume":"16","author":"Taniguchi","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.rinim.2014.08.001","article-title":"Establishment of c-myc-Immortalized Kupffer Cell Line from a C57BL\/6 Mouse Strain","volume":"4","author":"Kitani","year":"2014","journal-title":"Results Immunol."},{"key":"ref_71","first-page":"e52989","article-title":"Kupffer Cell Isolation for Nanoparticle Toxicity Testing","volume":"102","author":"Bourgognon","year":"2015","journal-title":"J. Vis. Exp."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5230\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:07:40Z","timestamp":1760137660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5230"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,7]]},"references-count":71,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095230"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095230","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,7]]}}}