دورية أكاديمية
Targeting oxidized phospholipids by AAV-based gene therapy in mice with established hepatic steatosis prevents progression to fibrosis.
| العنوان: | Targeting oxidized phospholipids by AAV-based gene therapy in mice with established hepatic steatosis prevents progression to fibrosis. |
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| المؤلفون: | Upchurch CM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Yeudall S; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Pavelec CM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA.; Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Merk D; Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany., Greulich J; Environmentally-Induced Cardiovascular Degeneration, Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, University Hospital and Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.; IUF-Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany., Manjegowda M; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Raghavan SS; Department of Pathology, University of Virginia, Charlottesville, VA 22904, USA., Bochkis IM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Scott MM; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Perez-Reyes E; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA., Leitinger N; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA.; Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22904, USA. |
| المصدر: | Science advances [Sci Adv] 2022 Jul 15; Vol. 8 (28), pp. eabn0050. Date of Electronic Publication: 2022 Jul 15. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| مواضيع طبية MeSH: | Non-alcoholic Fatty Liver Disease*/genetics , Non-alcoholic Fatty Liver Disease*/metabolism , Non-alcoholic Fatty Liver Disease*/therapy , Phospholipids*/metabolism, Animals ; Fibrosis ; Genetic Therapy ; Hepatocytes/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction |
| مستخلص: | Oxidized phosphatidylcholines (OxPCs) are implicated in chronic tissue damage. Hyperlipidemic LDL-R--deficient mice transgenic for an OxPC-recognizing IgM fragment (scFv-E06) are protected against nonalcoholic fatty liver disease (NAFLD). To examine the effect of OxPC elimination at different stages of NAFLD progression, we used cre-dependent, adeno-associated virus serotype 8-mediated expression of the single-chain variable fragment of E06 (AAV8-scFv-E06) in hepatocytes of albumin-cre mice. AAV8-induced expression of scFv-E06 at the start of FPC diet protected mice from developing hepatic steatosis. Independently, expression of scFv-E06 in mice with established steatosis prevented the progression to hepatic fibrosis. Mass spectrometry-based oxophospho-lipidomics identified individual OxPC species that were reduced by scFv-E06 expression. In vitro, identified OxPC species dysregulated mitochondrial metabolism and gene expression in hepatocytes and hepatic stellate cells. We demonstrate that individual OxPC species independently affect disease initiation and progression from hepatic steatosis to steatohepatitis, and that AAV-mediated expression of scFv-E06 is an effective therapeutic intervention. |
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| معلومات مُعتمدة: | T32 GM007267 United States GM NIGMS NIH HHS; P01 HL120840 United States HL NHLBI NIH HHS; R56 MH116694 United States MH NIMH NIH HHS; R01 NS097726 United States NS NINDS NIH HHS; T32 GM007055 United States GM NIGMS NIH HHS; T32 HL007284 United States HL NHLBI NIH HHS; R01 MH116694 United States MH NIMH NIH HHS; F30 HL154554 United States HL NHLBI NIH HHS |
| المشرفين على المادة: | 0 (Phospholipids) |
| تواريخ الأحداث: | Date Created: 20220720 Date Completed: 20220722 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC9286512 |
| DOI: | 10.1126/sciadv.abn0050 |
| PMID: | 35857497 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2375-2548 |
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| DOI: | 10.1126/sciadv.abn0050 |