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Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice
DC Field | Value | Language |
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dc.contributor.author | Choi, SE | - |
dc.contributor.author | Hwang, Y | - |
dc.contributor.author | Lee, SJ | - |
dc.contributor.author | Jung, H | - |
dc.contributor.author | Shin, TH | - |
dc.contributor.author | Son, Y | - |
dc.contributor.author | Park, S | - |
dc.contributor.author | Han, SJ | - |
dc.contributor.author | Kim, HJ | - |
dc.contributor.author | Lee, KW | - |
dc.contributor.author | Lee, G | - |
dc.contributor.author | Kemper, JK | - |
dc.contributor.author | Song, HK | - |
dc.contributor.author | Kang, Y | - |
dc.date.accessioned | 2023-03-24T06:26:57Z | - |
dc.date.available | 2023-03-24T06:26:57Z | - |
dc.date.issued | 2022 | - |
dc.identifier.issn | 0168-8278 | - |
dc.identifier.uri | http://repository.ajou.ac.kr/handle/201003/25101 | - |
dc.description.abstract | BACKGROUND & AIMS: Mitochondrial dysfunction is considered a pathogenic linker in the development of non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality control, possibly induced by insufficiency of the mitochondrial matrix caseinolytic protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate diet-induced NASH. METHODS: NASH was induced by a high-fat/high-fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate (PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown technique but increased through the viral transduction of ClpP. ClpP activation was induced by administering a chemical activator of ClpP. RESULTS: Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein levels in MPHs. Overexpression or activation of ClpP reversed PA/OA-induced mitochondrial dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown induced mitochondrial dysfunction and stress/inflammatory signals in these cells. On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed a HF/HFr diet. CONCLUSIONS: Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development of diet-induced NASH. ClpP supplementation through viral transduction or chemical activation represents a potential therapeutic strategy to prevent diet-induced NASH. LAY SUMMARY: Western diets, containing high fat and high fructose, often induce non-alcoholic steatohepatitis (NASH). Mitochondrial dysfunction is considered pathogenically linked to diet-induced NASH. We observed that the mitochondrial protease ClpP decreased in the livers of mice fed a western diet and supplementation of ClpP ameliorated western diet-induced NASH. | - |
dc.language.iso | en | - |
dc.subject.MESH | Animals | - |
dc.subject.MESH | Diet, High-Fat | - |
dc.subject.MESH | Dietary Supplements | - |
dc.subject.MESH | Disease Models, Animal | - |
dc.subject.MESH | Fructose | - |
dc.subject.MESH | Liver | - |
dc.subject.MESH | Mice | - |
dc.subject.MESH | Mice, Inbred C57BL | - |
dc.subject.MESH | Mitochondria | - |
dc.subject.MESH | Non-alcoholic Fatty Liver Disease | - |
dc.subject.MESH | Oleic Acid | - |
dc.subject.MESH | Peptide Hydrolases | - |
dc.title | Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice | - |
dc.type | Article | - |
dc.identifier.pmid | 35421426 | - |
dc.subject.keyword | inflammation | - |
dc.subject.keyword | mitochondrial dysfunction | - |
dc.subject.keyword | proteostasis | - |
dc.subject.keyword | steatohepatitis | - |
dc.contributor.affiliatedAuthor | Choi, SE | - |
dc.contributor.affiliatedAuthor | Han, SJ | - |
dc.contributor.affiliatedAuthor | Kim, HJ | - |
dc.contributor.affiliatedAuthor | Lee, KW | - |
dc.contributor.affiliatedAuthor | Lee, G | - |
dc.contributor.affiliatedAuthor | Kang, Y | - |
dc.type.local | Journal Papers | - |
dc.identifier.doi | 10.1016/j.jhep.2022.03.034 | - |
dc.citation.title | Journal of hepatology | - |
dc.citation.volume | 77 | - |
dc.citation.number | 3 | - |
dc.citation.date | 2022 | - |
dc.citation.startPage | 735 | - |
dc.citation.endPage | 747 | - |
dc.identifier.bibliographicCitation | Journal of hepatology, 77(3). : 735-747, 2022 | - |
dc.embargo.liftdate | 9999-12-31 | - |
dc.embargo.terms | 9999-12-31 | - |
dc.identifier.eissn | 1600-0641 | - |
dc.relation.journalid | J001688278 | - |
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