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During the development of NAFLD, Perilipin 5 (PLIN5) can regulate lipid metabolism by suppressing lipolysis and preventing lipotoxicity. Other reports suggest that the lack of PLIN5 decreases hepatic injury, indicating a protective role in NAFLD pathology. To better understand the role of PLIN5 in liver disease, we established mouse models of NAFLD and NAFLD-induced HCC, in which wild-type and <jats:italic>Plin5<\/jats:italic> null mice were exposed to a single dose of acetone or 7,12-dimethylbenz[a]anthracene (DMBA) in acetone, followed by a 30-week high-fat diet supplemented with glucose\/fructose. In the NAFLD model, RNA-seq revealed significant changes in genes related to lipid metabolism and immune response. At the intermediate level, pathways such as AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) were blunted in <jats:italic>Plin5-<\/jats:italic>deficient mice (<jats:italic>Plin5<\/jats:italic><jats:sup>\u2212<jats:italic>\/<\/jats:italic>\u2212<\/jats:sup>) compared to wild-type mice (WT). In the NAFLD-HCC model, only WT mice developed liver tumors, while <jats:italic>Plin5<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice were resistant to tumorigenesis. Furthermore, only 32 differentially expressed genes associated with NALFD progession were identified in <jats:italic>Plin5<\/jats:italic> null mice. The markers of mitochondrial function and immune response, such as the peroxisome proliferator\u2010activated receptor-\u03b3, coactivator 1\u2010\u03b1 (PGC-1\u03b1) and phosphorylated STAT3, were decreased. Lipidomic analysis revealed differential levels of some sphingomyelins between WT and <jats:italic>Plin5<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Interestingly, these changes were not detected in the HCC model, indicating a possible shift in the metabolism of sphingomelins during carcinogenesis.<\/jats:p>","DOI":"10.1038\/s41420-024-01860-4","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T17:02:33Z","timestamp":1708621353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9185-7613","authenticated-orcid":false,"given":"Paola Berenice","family":"Mass-Sanchez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marinela","family":"Krizanac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"\u0160tancl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin","family":"Leopold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0611-7042","authenticated-orcid":false,"given":"Kathrin M.","family":"Engel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva Miriam","family":"Buhl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"van Helden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Gassler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4328-8652","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Schiller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Karli\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"M\u00f6ckel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Twan","family":"Lammers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen K.","family":"Meurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Asimakopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,22]]},"reference":[{"key":"1860_CR1","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.3350\/cmh.2022.0365","volume":"29","author":"ML Teng","year":"2023","unstructured":"Teng ML, Ng CH, Huang DQ, Chan KE, Tan DJ, Lim WH, et al. 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