A novel peptide encoded by circ‐SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac‐mediated CD36 transcription in NAFLD
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BACKGROUND: As the leading cause of end-stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined. METHODS: Combined high-throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull-down/MS and site-specific mutagenesis. RESULTS: In this study, we focused on circ-SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6-126aa in vivo and in vitro. YTHDF2-mediated degradation of m6A-modified circ-SLC9A6 was found to be essential for the regulation of SLC9A6-126aa expression. We further found that the phosphorylation of SLC9A6-126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high-fat stress induced substantial translocation of unphosphorylated SLC9A6-126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6-126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF-mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6-126aa transgenic mice. Clinically, increasing levels of SLC9A6-126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades. CONCLUSION: This study revealed the role of circ-SLC9A6-derived SLC9A6-126aa in the epigenetic modification-mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases. HIGHLIGHTS: Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ-SLC9A6, thereby inhibiting the translation of SLC9A6-126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6-126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6-126aa. Nuclear SLC9A6-126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- A novel peptide encoded by circ‐SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac‐mediated CD36 transcription in NAFLD
- Date Crossref
- 01/08/2024
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Dalian Medical University Department of Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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Second Affiliated Hospital of Zhejiang University pays non établi dans la noticeÉtablissement de santé
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First Affiliated Hospital Zhejiang University pays non établi dans la noticeÉtablissement de santé
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Second Affiliated Hospital of Dalian Medical University pays non établi dans la noticeÉtablissement de santé
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Hangzhou Red Cross Hospital pays non établi dans la noticeÉtablissement de santé
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Yue Wang and Xinyao Tian contributed equally to this work pays non établi dans la noticeInstitution
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Department of Surgery Division of Hepatobiliary and Pancreatic Surgery The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou China Department of Surgery pays non établi dans la noticeUniversité ou école supérieure
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Department of Hepatobiliary and Pancreatic Surgery Department of Liver Transplantation Shulan (Hangzhou) Hospital Hangzhou China Department of Hepatobiliary and Pancreatic Surgery pays non établi dans la noticeÉtablissement de santé
Department of Pharmacology — Dalian Medical University, Second Affiliated Hospital of Zhejiang University et First Affiliated Hospital Zhejiang University, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.