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Deeper investigations are needed to determine the potential impact of plant miRNAs in NAFLD. This study aimed to identify plant miRNAs that could eventually modulate the expression of human metabolic genes and protect against the progression of hepatic steatosis. Plant miRNAs from the miRBase were used to predict human target genes, and miR8126-3p and miR8126-5p were selected as candidates for their potential role in inhibiting glucose and lipid metabolism-related genes. Human HepG2 cells were transfected with plant miRNA mimics and then exposed to a mixture of oleic and palmitic acids to mimic steatosis. miR8126-3p and miR8126-5p transfections inhibited the expression of the putative target genes QKI and MAPKAPK2, respectively, and had an impact on the expression profile of key metabolic genes, including PPARA and SREBF1. Quantification of intrahepatic triglycerides revealed that miR8126-3p and miR8126-5p attenuated lipid accumulation. These findings suggest that plant miR8126-3p and miR8126-5p would induce metabolic changes in human hepatocytes eventually protecting against lipid accumulation, and thus, they could be potential therapeutic tools for preventing and alleviating lipid accumulation.<\/jats:p>","DOI":"10.3390\/ijms25031721","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T08:44:06Z","timestamp":1706690646000},"page":"1721","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Plant miR8126-3p and miR8126-5p Decrease Lipid Accumulation through Modulation of Metabolic Genes in a Human Hepatocyte Model That Mimics Steatosis"],"prefix":"10.3390","volume":"25","author":[{"given":"Ester","family":"D\u00edez-Sainz","sequence":"first","affiliation":[{"name":"Department of Nutrition, Food Science and Physiology, and Center for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1282-0079","authenticated-orcid":false,"given":"Paula","family":"Aranaz","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Food Science and Physiology, and Center for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8426-5396","authenticated-orcid":false,"given":"Ez-Zoubir","family":"Amri","sequence":"additional","affiliation":[{"name":"CNRS, Inserm, iBV, Universit\u00e9 C\u00f4te d\u2019Azur, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1885-8457","authenticated-orcid":false,"given":"Jos\u00e9 I.","family":"Riezu-Boj","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Food Science and Physiology, and Center for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1033-6152","authenticated-orcid":false,"given":"Silvia","family":"Lorente-Cebri\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Health and Sport Science, University of Zaragoza, 50009 Zaragoza, Spain"},{"name":"Instituto Agroalimentario de Arag\u00f3n-IA2, Universidad de Zaragoza-Centro de Investigaci\u00f3n y Tecnolog\u00eda Agroalimentaria (CITA), 50013 Zaragoza, Spain"},{"name":"Arag\u00f3n Health Research Institute (IIS-Aragon), 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3228-9916","authenticated-orcid":false,"given":"Ferm\u00edn I.","family":"Milagro","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Food Science and Physiology, and Center for Nutrition Research, Faculty of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain"},{"name":"Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3313","DOI":"10.1007\/s00018-018-2860-6","article-title":"Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease","volume":"75","author":"Ipsen","year":"2018","journal-title":"Cell. 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