{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:18:22Z","timestamp":1787563102559,"version":"build-2736575974"},"reference-count":47,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370575"],"award-info":[{"award-number":["82370575"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Excessive fatty acids in the liver lead to the accumulation of lipotoxic lipids and then cellular stress to further evoke the related disease, like non\u2010alcoholic fatty liver disease (NAFLD). As reported, fatty acid stimulation can cause some specific miRNA dysregulation, which caused us to investigate the relationship between miRNA biogenesis and fatty acid overload.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Gene expression omnibus (GEO) dataset analysis, miRNA\u2010seq, miRNA cleavage assay, RT\u2010qPCR, western blotting, immunofluorescence and co\u2010immunoprecipitation (co\u2010IP) were used to reveal the change of miRNAs under pathological status and explore the relevant mechanism. High fat, high fructose, high cholesterol (HFHFrHC) diet\u2010fed mice transfected with AAV2\/8\u2010shDrosha or AAV2\/8\u2010shPRMT5 were established to investigate the in\u00a0vivo effects of Drosha or PRMT5 on NAFLD phenotype.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We discovered that the cleavage of miRNAs was inhibited by analysing miRNA contents and detecting some representative pri\u2010miRNAs in multiple mouse and cell models, which was further verified by the reduction of the Microprocessor activity in the presence of palmitic acid (PA). In\u00a0vitro, PA could induce Drosha, the core RNase III in the Microprocessor complex, degrading through the proteasome\u2010mediated pathway, while in\u00a0vivo, knockdown of Drosha significantly promoted NAFLD to develop to a more serious stage. Mechanistically, our results demonstrated that PA can increase the methyltransferase activity of PRMT5 to degrade Drosha through MDM2, a ubiquitin E3 ligase for Drosha. The above results indicated that PRMT5 may be a critical regulator in lipid metabolism during NAFLD, which was confirmed by the knocking down of PRMT5 improved aberrant lipid metabolism in\u00a0vitro and in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We first demonstrated the relationship between miRNA dosage and NAFLD and proved that PA can activate the PRMT5\u2010MDM2\u2010Drosha signalling pathway to regulate miRNA biogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.15906","type":"journal-article","created":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T08:50:29Z","timestamp":1711097429000},"page":"1634-1650","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Excessive fatty acids activate\n                    <scp>PRMT5<\/scp>\n                    \/\n                    <scp>MDM2<\/scp>\n                    \/Drosha pathway to regulate\n                    <scp>miRNA<\/scp>\n                    biogenesis and lipid metabolism"],"prefix":"10.1111","volume":"44","author":[{"given":"Aijun","family":"Hou","sequence":"first","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences  Shanghai China"},{"name":"School of Pharmacy University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoding","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences  Shanghai China"},{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 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