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Significant increases in the levels of miRNA-21 in both liver tissues and plasma have been observed in APAP-overdosed animals and humans. However, the mechanistic effect of miRNA-21 on acute liver injury remains unknown. In this study, we generated a new hepatocyte-specific miRNA-21 knockout (miR-21-HKO) mouse line. miR-21-HKO and the background-matched sibling wild-type (WT) mice were treated with a toxic dose of APAP. Compared with WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3 beta, which suggested an autophagy activation. The expression of PPAR\u03b3 was highly induced in the livers of miR-21-HKO mice after a 2-h APAP treatment, which preceded the activation of LC3B at the 12\u2009h APAP treatment. miR-21 negatively regulated PPAR\u03b3 protein expression by targeting its 3\u2032-UTR. When PPAR\u03b3 function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPAR\u03b3 signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPAR\u03b3 and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury.<\/jats:p>","DOI":"10.1093\/toxsci\/kfad132","type":"journal-article","created":{"date-parts":[[2024,1,5]],"date-time":"2024-01-05T17:53:55Z","timestamp":1704477235000},"page":"50-60","source":"Crossref","is-referenced-by-count":6,"title":["Hepatocyte miR-21-5p-deficiency alleviates APAP-induced liver injury by inducing PPAR\u03b3 and autophagy"],"prefix":"10.1093","volume":"198","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6743-8881","authenticated-orcid":false,"given":"Chao","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University , Jinan, Shandong, 250021,","place":["China"]},{"name":"Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism , Jinan, Shandong, 250021,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pain Management, Shandong Provincial Hospital affiliated to Shandong First Medical University , Jinan, Shandong, 250021,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang, 310009,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8695-6980","authenticated-orcid":false,"given":"Hartmut","family":"Jaeschke","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center , Kansas City, Kansas 66160,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguo","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic , Cleveland, Ohio 44195,","place":["USA"]},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University , Cleveland, Ohio 44195,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University , Jinan, Shandong, 250021,","place":["China"]},{"name":"Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism , Jinan, Shandong, 250021,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University , Jinan, Shandong, 250021,","place":["China"]},{"name":"Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism , Jinan, Shandong, 250021,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanfei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University , Beijing, 100029,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Independent Researcher , Tucson, Arizona 85004,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,5]]},"reference":[{"key":"2024102110193125700_kfad132-B1","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.jhep.2007.07.030","article-title":"Importance of peroxisome proliferator-activated receptor-gamma in hepatic ischemia\/reperfusion injury in mice","volume":"47","author":"Akahori","year":"2007","journal-title":"J. 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