{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:06:38Z","timestamp":1780657598133,"version":"3.54.1"},"reference-count":36,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T00:00:00Z","timestamp":1698710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.81973034"],"award-info":[{"award-number":["No.81973034"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The etiology of numerous metabolic disorders is characterized by hepatic insulin resistance (IR). Uncertainty surrounds miR-34a\u2019s contribution to high-fat-induced hepatic IR and its probable mechanism. The role and mechanism of miR-34a and its target gene ENO3 in high-fat-induced hepatic IR were explored by overexpressing\/suppressing miR-34a and ENO3 levels in in vivo and in vitro experiments. Moreover, as a human hepatic IR model, the miR-34a\/ENO3 pathway was validated in patients with non-alcoholic fatty liver disease (NAFLD). The overexpression of hepatic miR-34a lowered insulin signaling and altered glucose metabolism in hepatocytes. In contrast, reducing miR-34a expression significantly reversed hepatic IR indices induced by palmitic acid (PA)\/HFD. ENO3 was identified as a direct target gene of miR-34a. Overexpression of ENO3 effectively inhibited high-fat-induced hepatic IR-related indices both in vitro and in vivo. Moreover, the expression patterns of members of the miR-34a\/ENO3 pathway in the liver tissues of NAFLD patients was in line with the findings of both cellular and animal studies. A high-fat-induced increase in hepatic miR-34a levels attenuates insulin signaling and impairs glucose metabolism by suppressing the expression of its target gene ENO3, ultimately leading to hepatic IR. The miR-34a\/ENO3 pathway may be a potential therapeutic target for hepatic IR and related metabolic diseases.<\/jats:p>","DOI":"10.3390\/nu15214616","type":"journal-article","created":{"date-parts":[[2023,10,31]],"date-time":"2023-10-31T12:48:31Z","timestamp":1698756511000},"page":"4616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["MicroRNA-34a Mediates High-Fat-Induced Hepatic Insulin Resistance by Targeting ENO3"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5086-3777","authenticated-orcid":false,"given":"Yuanyuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kening","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangshuang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.cmet.2017.08.002","article-title":"Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases","volume":"27","author":"Samuel","year":"2018","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.tips.2017.04.004","article-title":"Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance","volume":"38","author":"Petersen","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/hep.26672","article-title":"Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes","volume":"59","author":"Birkenfeld","year":"2014","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrg2843","article-title":"The widespread regulation of microRNA biogenesis, function and decay","volume":"11","author":"Krol","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev-biochem-060308-103103","article-title":"Regulation of mRNA translation and stability by microRNAs","volume":"79","author":"Fabian","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1002\/wrna.1240","article-title":"Influence of miRNA in insulin signaling pathway and insulin resistance: Micro-molecules with a major role in type-2 diabetes","volume":"5","author":"Chakraborty","year":"2014","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ebiom.2019.03.041","article-title":"Down-regulation of MicroRNA-592 in obesity contributes to hyperglycemia and insulin resistance","volume":"42","author":"Song","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6052","DOI":"10.1002\/jcp.26442","article-title":"Hepatic miR-125b inhibits insulin signaling pathway by targeting PIK3CD","volume":"233","author":"Du","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3748\/wjg.v21.i2.511","article-title":"miRNA-103: Molecular link between insulin resistance and nonalcoholic fatty liver disease","volume":"21","author":"Xu","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13046-019-1059-5","article-title":"MicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer","volume":"38","author":"Zhang","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1093\/jmcb\/mju003","article-title":"The p53\/miR-34 axis in development and disease","volume":"6","author":"Rokavec","year":"2014","journal-title":"J. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00592-010-0226-0","article-title":"Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: A clinical study","volume":"48","author":"Kong","year":"2011","journal-title":"Acta Diabetol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10238-019-00593-4","article-title":"Senescence-associated miR-34a and miR-126 in middle-aged Indians with type 2 diabetes","volume":"20","author":"Banerjee","year":"2020","journal-title":"Clin. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1111\/1440-1681.13147","article-title":"Circulating miR-146a, miR-34a and miR-375 in type 2 diabetes patients, pre-diabetic and normal-glycaemic individuals in relation to beta-cell function, insulin resistance and metabolic parameters","volume":"46","year":"2019","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s12263-019-0630-1","article-title":"High-throughput sequencing of small RNAs and analysis of differentially expressed microRNAs associated with high-fat diet-induced hepatic insulin resistance in mice","volume":"14","author":"Zhao","year":"2019","journal-title":"Genes Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liu, H., Zhu, R., Liu, C., Ma, R., Wang, L., Chen, B., Li, L., Niu, J., Zhao, D., and Mo, F. (2017). Evaluation of Decalcification Techniques for Rat Femurs Using HE and Immunohistochemical Staining. BioMed Res. Int., 2017.","DOI":"10.1155\/2017\/9050754"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.freeradbiomed.2023.02.017","article-title":"ETNPPL impairs autophagy through regulation of the ARG2-ROS signaling axis, contributing to palmitic acid-induced hepatic insulin resistance","volume":"199","author":"Wang","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3389\/fgene.2014.00023","article-title":"Common features of microRNA target prediction tools","volume":"5","author":"Peterson","year":"2014","journal-title":"Front. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/978-1-62703-083-0_10","article-title":"Evaluating the microRNA targeting sites by luciferase reporter gene assay","volume":"936","author":"Jin","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11526","DOI":"10.1021\/jf802607x","article-title":"Gossypin up-regulates LDL receptor through activation of ERK pathway: A signaling mechanism for the hypocholesterolemic effect","volume":"56","author":"Lu","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S173","DOI":"10.1002\/mnfr.201100064","article-title":"Long-term adaptation of global transcription and metabolism in the liver of high-fat diet-fed C57BL\/6J mice","volume":"55","author":"Do","year":"2011","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_22","first-page":"200","article-title":"Protective Role of trans-Chalcone against the Progression from Simple Steatosis to Non-alcoholic Steatohepatitis: Regulation of miR-122, 21, 34a, and 451","volume":"12","author":"Jeddi","year":"2022","journal-title":"Adv. Pharm. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1007\/s00535-016-1178-0","article-title":"A micro-RNA expression signature for human NAFLD progression","volume":"51","author":"Guo","year":"2016","journal-title":"J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3960197","DOI":"10.1155\/2017\/3960197","article-title":"circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis","volume":"2017","author":"Guo","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"eaao4617","DOI":"10.1126\/scisignal.aao4617","article-title":"IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs","volume":"11","author":"Wang","year":"2018","journal-title":"Sci. Signal"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.2337\/diabetes.50.1.24","article-title":"Serine\/threonine phosphorylation of IRS-1 triggers its degradation: Possible regulation by tyrosine phosphorylation","volume":"50","author":"Pederson","year":"2001","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.1210\/endo.139.12.6348","article-title":"Differential regulation of insulin receptor substrate-2 and mitogen-activated protein kinase tyrosine phosphorylation by phosphatidylinositol 3-kinase inhibitors in SH-SY5Y human neuroblastoma cells","volume":"139","author":"Kim","year":"1998","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1007\/s00125-012-2644-8","article-title":"Regulation of insulin sensitivity by serine\/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2","volume":"55","author":"Copps","year":"2012","journal-title":"Diabetologia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1007\/s00125-020-05212-6","article-title":"Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes","volume":"63","author":"Krause","year":"2020","journal-title":"Diabetologia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5944","DOI":"10.1021\/ac1001959","article-title":"Diagnostic detection of human lung cancer-associated antigen using a gold nanoparticle-based electrochemical immunosensor","volume":"82","author":"Ho","year":"2010","journal-title":"Anal. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1107\/S2053230X17004022","article-title":"Crystal structure of enolase from Drosophila melanogaster","volume":"73","author":"Sun","year":"2017","journal-title":"Acta Crystallogr. F Struct. Biol. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/ana.1095","article-title":"Beta-enolase deficiency, a new metabolic myopathy of distal glycolysis","volume":"50","author":"Comi","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"111213","DOI":"10.1016\/j.mad.2020.111213","article-title":"Physical exercise increases ROCK activity in the skeletal muscle of middle-aged rats","volume":"186","author":"Munoz","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1210\/er.2019-00034","article-title":"The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance","volume":"40","author":"Watt","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wen, W., Wu, P., Zhang, Y., Chen, Z., Sun, J., and Chen, H. (2021). Comprehensive Analysis of NAFLD and the Therapeutic Target Identified. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.704704"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"G439","DOI":"10.1152\/ajpgi.00397.2020","article-title":"Noninvasive stratification of nonalcoholic fatty liver disease by whole transcriptome cell-free mRNA characterization","volume":"320","author":"Chalasani","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/21\/4616\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:14:36Z","timestamp":1760130876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/21\/4616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,31]]},"references-count":36,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["nu15214616"],"URL":"https:\/\/doi.org\/10.3390\/nu15214616","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,31]]}}}