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This study examined the functional contribution and molecular mechanism of miR-27a in regulating hepatocyte mitochondrial homeostasis and lipid metabolism. Utilizing in vivo mouse models, including low-fat diet controls, high-fat diet (HFD)-induced obesity, and gain- and loss-of-function approaches, miR-27a was found to be markedly upregulated in the serum and liver of obese mice, correlating with disrupted glucose and lipid homeostasis as well as hepatic steatosis. Mechanistically, miR-27a overexpression recapitulated HFD-induced mitochondrial dysfunction, manifested by decreased mitochondrial biogenesis and elevated reactive oxygen species (ROS) production. Conversely, genetic silencing of miR-27a restored mitochondrial integrity and mitigated lipid accumulation. In vitro experiments using HepG2 cells confirmed that miR-27a directly suppresses nuclear factor erythroid 2-related factor 2 (NFE2L2), and NFE2L2 overexpression counteracted miR-27a-induced mitochondrial damage and steatosis. Collectively, these results demonstrate that miR-27a promotes hepatic steatosis by targeting NFE2L2, leading to mitochondrial impairment and oxidative stress, highlighting miR-27a as a potential biomarker and therapeutic target for obesity-associated liver metabolic disorders.<\/jats:p>","DOI":"10.3390\/molecules31101753","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:12:54Z","timestamp":1779286374000},"page":"1753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["miR-27a Suppresses Mitochondrial Function to Promote Hepatic Steatosis in High-Fat-Diet-Induced Obesity"],"prefix":"10.3390","volume":"31","author":[{"given":"Zhiyi","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"},{"name":"Department of Physiology and Pharmacology, Basic Medical College, Changchun Medical College, Changchun 130031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meishuang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"},{"name":"Department of Rehabilitation, School of Nursing, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7753-5965","authenticated-orcid":false,"given":"Siwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengying","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/ncp.10449","article-title":"Evolution of NAFLD and Its Management","volume":"35","author":"Mundi","year":"2020","journal-title":"Nutr. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: A tale of two \u201chits\u201d?","volume":"114","author":"Day","year":"1998","journal-title":"Gastroenterology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Masarone, M., Rosato, V., Dallio, M., Gravina, A.G., Aglitti, A., Loguercio, C., Federico, A., and Persico, M. (2018). Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease. Oxid. Med. Cell Longev., 2018.","DOI":"10.1155\/2018\/9547613"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1136\/gutjnl-2018-318146","article-title":"miRNAs and NAFLD: From pathophysiology to therapy","volume":"68","author":"Gjorgjieva","year":"2019","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.dld.2014.09.020","article-title":"Nonalcoholic fatty liver disease: A precursor of the metabolic syndrome","volume":"47","author":"Lonardo","year":"2015","journal-title":"Dig. Liver Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1042\/bse0470069","article-title":"Regulation of mitochondrial biogenesis","volume":"47","author":"Jornayvaz","year":"2010","journal-title":"Essays Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1080\/21623945.2016.1273298","article-title":"Stress turns on the heat: Regulation of mitochondrial biogenesis and UCP1 by ROS in adipocytes","volume":"6","author":"Ortega","year":"2017","journal-title":"Adipocyte"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/febs.13820","article-title":"Mitochondrial biogenesis and clearance: A balancing act","volume":"284","author":"Ploumi","year":"2017","journal-title":"FEBS J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liu, L., Locascio, L.M., and Dor\u00e9, S. (2019). Critical Role of Nrf2 in Experimental Ischemic Stroke. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00153"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.bbagen.2014.11.021","article-title":"Nrf2 regulates ROS production by mitochondria and NADPH oxidase","volume":"1850","author":"Kovac","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Qiu, M., Xiao, F., Wang, T., Piao, S., Zhao, W., Shao, S., Yan, M., and Zhao, D. (2020). Protective effect of Hedansanqi Tiaozhi Tang against non-alcoholic fatty liver disease in vitro and in vivo through activating Nrf2\/HO-1 antioxidant signaling pathway. Phytomedicine, 67.","DOI":"10.1016\/j.phymed.2019.153140"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.1111\/jcmm.14293","article-title":"Aucubin inhibited lipid accumulation and oxidative stress via Nrf2\/HO-1 and AMPK signalling pathways","volume":"23","author":"Shen","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1080\/15548627.2020.1712108","article-title":"SQSTM1\/p62 activates NFE2L2\/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity","volume":"16","author":"Lee","year":"2020","journal-title":"Autophagy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ajog.2017.10.040","article-title":"Oxidative stress-induced miR-27a targets the redox gene nuclear factor erythroid 2-related factor 2 in diabetic embryopathy","volume":"218","author":"Zhao","year":"2018","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.biopha.2018.08.002","article-title":"Omentin-1 protects renal function of mice with type 2 diabetic nephropathy via regulating miR-27a-Nrf2\/Keap1 axis","volume":"107","author":"Song","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.7150\/thno.22565","article-title":"Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPAR\u03b3","volume":"8","author":"Yu","year":"2018","journal-title":"Theranostics"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ando, Y., Yamazaki, M., Yamada, H., Munetsuna, E., Fujii, R., Mizuno, G., Ichino, N., Osakabe, K., Sugimoto, K., and Ishikawa, H. (2019). Association of circulating miR-20a, miR-27a, and miR-126 with non-alcoholic fatty liver disease in general population. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-55076-z"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.18632\/oncotarget.23262","article-title":"MiR-27a as a predictor for the activation of hepatic stellate cells and hepatitis B virus-induced liver cirrhosis","volume":"9","author":"Zhang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/iub.2221","article-title":"Inhibiting miR-27a and miR-142-5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway","volume":"72","author":"Teimouri","year":"2020","journal-title":"IUBMB Life"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1053\/j.gastro.2017.08.013","article-title":"Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues","volume":"153","author":"Chai","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1016\/j.celrep.2018.01.074","article-title":"Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance","volume":"22","author":"Price","year":"2018","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1136\/gutjnl-2015-310822","article-title":"Stress-activated miR-21\/miR-21* in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption","volume":"65","author":"Calo","year":"2016","journal-title":"Gut"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12158","DOI":"10.1073\/pnas.1808855115","article-title":"Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice","volume":"115","author":"Kalko","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.bbrc.2015.07.051","article-title":"rhTNFR:Fc increases Nrf2 expression via miR-27a mediation to protect myocardium against sepsis injury","volume":"464","author":"Xue","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1152\/physiolgenomics.00041.2017","article-title":"Nrf2 at the heart of oxidative stress and cardiac protection","volume":"50","author":"Chen","year":"2018","journal-title":"Physiol. Genom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.cell.2015.10.001","article-title":"Mitochondrial ROS signaling in organismal homeostasis","volume":"163","author":"Shadel","year":"2015","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.freeradbiomed.2015.04.036","article-title":"The emerging role of Nrf2 in mitochondrial function","volume":"88","author":"Abramov","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1152\/physrev.00025.2007","article-title":"Transcriptional paradigms in mammalian mitochondrial biogenesis and function","volume":"88","author":"Scarpulla","year":"2008","journal-title":"Physiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kiyama, T., Chen, C.K., Wang, S.W., Pan, P., Ju, Z., Wang, J., Takada, S., Klein, W.H., and Mao, C.A. (2018). Essential roles of mitochondrial biogenesis regulator Nrf1 in retinal development and homeostasis. Mol. Neurodegener., 13.","DOI":"10.1186\/s13024-018-0287-z"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kang, T., Lu, W., Xu, W., Anderson, L., Bacanamwo, M., Thompson, W., Chen, Y.E., and Liu, D. (2020). Correction: MicroRNA-27 (miR-27) targets prohibitin and impairs adipocyte differentiation and mitochondrial function in human adipose-derived stem cells. J. Biol. Chem., 295.","DOI":"10.1074\/jbc.AAC120.016601"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Barisciano, G., Leo, M., Muccillo, L., Pranzini, E., Parri, M., Colantuoni, V., Taddei, M.L., and Sabatino, L. (2021). The miR-27a\/FOXJ3 Axis Dysregulates Mitochondrial Homeostasis in Colorectal Cancer Cells. Cancers, 13.","DOI":"10.3390\/cancers13194994"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chen, D., Li, X., Zhang, L., Zhu, M., and Gao, L. (2018). A high-fat diet impairs mitochondrial biogenesis, mitochondrial dynamics, and the respiratory chain complex in rat myocardial tissues. J. Cell Biochem., 119.","DOI":"10.1002\/jcb.27068"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/978-1-61779-959-4_11","article-title":"Phosphoproteomic analysis of liver homogenates","volume":"909","author":"Demirkan","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s12094-022-02965-x","article-title":"Hypoxia promotes epithelial-mesenchymal transition in lung cancer cells via regulating the NRF2\/miR-27a\/BUB1 pathway","volume":"25","author":"Liu","year":"2023","journal-title":"Clin. Transl. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1111\/dom.16102","article-title":"Islet-derived exosomal miR-204 accelerates insulin resistance in skeletal muscle by suppressing sirtuin 1: An in vivo study in a mouse model of high-fat diet-induced obesity","volume":"27","author":"Yang","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Paemanee, A., Sornjai, W., Kittisenachai, S., Sirinonthanawech, N., Roytrakul, S., Wongtrakul, J., and Smith, D.R. (2017). Nevirapine induced mitochondrial dysfunction in HepG2 cells. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-09321-y"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.1471-4159.2011.07581.x","article-title":"Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"120","author":"Sheng","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Ignatenko, O., Chilov, D., Paetau, I., de Miguel, E., Jackson, C.B., Capin, G., Paetau, A., Terzioglu, M., Euro, L., and Suomalainen, A. (2018). Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy. Nat. Commun., 9.","DOI":"10.1038\/s41467-017-01859-9"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1753\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T04:10:44Z","timestamp":1779682244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":40,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["molecules31101753"],"URL":"https:\/\/doi.org\/10.3390\/molecules31101753","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}