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To evaluate its effect on the hepatic transcriptome, RNA sequencing was carried out in two groups of male Large White x Landrace pigs developing nonalcoholic steatohepatitis by feeding them a high fat\/cholesterol\/fructose and methionine and choline-deficient steatotic diet or the same diet with 0.5% squalene. Hepatic lipids, squalene content, steatosis, activity (ballooning + inflammation), and SAF (steatosis + activity + fibrosis) scores were analyzed. Pigs receiving the latter diet showed hepatic squalene accumulation and twelve significantly differentially expressed hepatic genes (log2 fold change &lt; 1.5 or &lt;1.5) correlating in a gene network. These pigs also had lower hepatic triglycerides and lipid droplet areas and higher cellular ballooning. Glutamyl aminopeptidase (ENPEP) was correlated with triglyceride content, while alpha-fetoprotein (AFP), neutralized E3 ubiquitin protein ligase 3 (NEURL3), 2\u2032-5\u2032-oligoadenylate synthase-like protein (OASL), and protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B) were correlated with activity reflecting inflammation and ballooning, and NEURL3 with the SAF score. AFP, ENPEP, and PPP1R1B exhibited a remarkably strong discriminant power compared to those pathological parameters in both experimental groups. Moreover, the expression of PPP1R1B, TMEM45B, AFP, and ENPEP followed the same pattern in vitro using human hepatoma (HEPG2) and mouse liver 12 (AML12) cell lines incubated with squalene, indicating a direct effect of squalene on these expressions. These findings suggest that squalene accumulated in the liver is able to modulate gene expression changes that may influence the progression of non-alcoholic steatohepatitis.<\/jats:p>","DOI":"10.3390\/ijms241612552","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:26:39Z","timestamp":1691497599000},"page":"12552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Differentially Expressed Genes in Response to a Squalene-Supplemented Diet Are Accurate Discriminants of Porcine Non-Alcoholic Steatohepatitis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1087-8150","authenticated-orcid":false,"given":"Roubi","family":"Abuobeid","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de 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Spain"},{"name":"CIBER de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, E-28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-5000","authenticated-orcid":false,"given":"Seyed Hesamoddin","family":"Bidooki","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA-Universidad de Zaragoza, E-50013 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9023-741X","authenticated-orcid":false,"given":"Javier","family":"S\u00e1nchez-Marco","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Facultad de Veterinaria, 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Universidad de Zaragoza, E-22071 Huesca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3595-7668","authenticated-orcid":false,"given":"Mar\u00eda Jes\u00fas","family":"Rodr\u00edguez-Yoldi","sequence":"additional","affiliation":[{"name":"Instituto Agroalimentario de Arag\u00f3n, CITA-Universidad de Zaragoza, E-50013 Zaragoza, Spain"},{"name":"CIBER de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, E-28029 Madrid, Spain"},{"name":"Departamento de Farmacolog\u00eda, Fisiolog\u00eda, Medicina Legal y Forense, Facultad de Veterinaria, Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n, Universidad de Zaragoza, E-50013 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8100-5596","authenticated-orcid":false,"given":"Roberto","family":"Mart\u00ednez-Beamonte","sequence":"additional","affiliation":[{"name":"Departamento de 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