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Article: Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer

TitleApobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer
Authors
KeywordsHepatology
Liver cancer
Metabolism
RNA processing
Issue Date2021
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal of Clinical Investigation, 2021, v. 131 n. 1, p. article no. e138699 How to Cite?
AbstractThe RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1–/–, and A1cf–/– mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC.
Persistent Identifierhttp://hdl.handle.net/10722/304799
ISSN
2023 Impact Factor: 13.3
2023 SCImago Journal Rankings: 4.833
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBlanc, V-
dc.contributor.authorRiordan, JD-
dc.contributor.authorSoleymanjahi, S-
dc.contributor.authorNadeau, JH-
dc.contributor.authorNalbantoglu, I-
dc.contributor.authorXie, Y-
dc.contributor.authorMolitor, EA-
dc.contributor.authorMadison, BB-
dc.contributor.authorBrunt, EM-
dc.contributor.authorMills, JC-
dc.contributor.authorRubin, DC-
dc.contributor.authorNg, IO-
dc.contributor.authorHa, Y-
dc.contributor.authorRoberts, LR-
dc.contributor.authorDavidson, NO-
dc.date.accessioned2021-10-05T02:35:22Z-
dc.date.available2021-10-05T02:35:22Z-
dc.date.issued2021-
dc.identifier.citationJournal of Clinical Investigation, 2021, v. 131 n. 1, p. article no. e138699-
dc.identifier.issn0021-9738-
dc.identifier.urihttp://hdl.handle.net/10722/304799-
dc.description.abstractThe RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1–/–, and A1cf–/– mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC.-
dc.languageeng-
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org-
dc.relation.ispartofJournal of Clinical Investigation-
dc.subjectHepatology-
dc.subjectLiver cancer-
dc.subjectMetabolism-
dc.subjectRNA processing-
dc.titleApobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer-
dc.typeArticle-
dc.identifier.emailNg, IO: iolng@hku.hk-
dc.identifier.authorityNg, IO=rp00335-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1172/JCI138699-
dc.identifier.pmid33445170-
dc.identifier.pmcidPMC7773377-
dc.identifier.scopuseid_2-s2.0-85098889981-
dc.identifier.hkuros325813-
dc.identifier.volume131-
dc.identifier.issue1-
dc.identifier.spagearticle no. e138699-
dc.identifier.epagearticle no. e138699-
dc.identifier.isiWOS:000607655600002-
dc.publisher.placeUnited States-

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