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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. [ABSTRACT FROM AUTHOR]

Damaged mitochondria, a key factor in liver fibrosis, can be removed by the mitophagy pathway to maintain homeostasis of the intracellular environment to alleviate the development of fibrosis. PINK1 (PTEN‐induced kinase 1) and NIPSNAP1 (nonneuronal SNAP25‐like protein 1), which cooperatively regulate mitophagy, have been predicted to include the sites of lysine acetylation related to SIRT3 (mitochondrial deacetylase sirtuin 3). Our study aimed to discuss whether SIRT3 deacetylates PINK1 and NIPSNAP1 to regulate mitophagy in liver fibrosis. Carbon tetrachloride (CCl4)‐induced liver fibrosis as an in vivo model and LX‐2 cells as activated cells were used to simulate liver fibrosis. SIRT3 expression was significantly decreased in mice in response to CCl4, and SIRT3 knockout in vivo significantly deepened the severity of liver fibrosis, as indicated by increased α‐SMA and Col1a1 levels both in vivo and in vitro. SIRT3 overexpression decreased α‐SMA and Col1a1 levels. Furthermore, SIRT3 significantly regulated mitophagy in liver fibrosis, as demonstrated by LC3‐Ⅱ/Ⅰ and p62 expression and colocalization between TOM20 and LAMP1. Importantly, PINK1 and NIPSNAP1 expression was also decreased in liver fibrosis, and PINK1 and NIPSNAP1 overexpression significantly improved mitophagy and attenuated ECM production. Furthermore, after simultaneously interfering with PINK1 or NIPSNAP1 and overexpressing SIRT3, the effect of SIRT3 on improving mitophagy and alleviating liver fibrosis was disrupted. Mechanistically, we show that SIRT3, as a mitochondrial deacetylase, specifically regulates the acetylation of PINK1 and NIPSNAP1 to mediate the mitophagy pathway in liver fibrosis. SIRT3‐mediated PINK1 and NIPSNAP1 deacetylation is a novel molecular mechanism in liver fibrosis. [ABSTRACT FROM AUTHOR]

Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and antiadipogenic properties. Here, we investigate the molecular mechanism by which CA inhibits hydrogen peroxide ([H.sub.2][O.sub.2])-induced injury in HepG2 cells. Cells were pretreated with 2.5-10 µmol/L CA for 2 h and then exposed to 3 mmol/L [H.sub.2][O.sub.2] for an additional 4 h. CA dose-dependently increased cell viability and decreased lactate dehydrogenase activities. Pretreatment with CA completely attenuated the inhibited expression of manganese superoxide dismutase (MnSOD) and the B-cell lymphoma-extra large (Bcl-xL), and reduced glutathione activity caused by [H.sub.2][O.sub.2], whereas it reversed reactive oxygen species accumulation and the increase in cleaved caspase-3. Importantly, sirtuin 1 (SIRT1), a [NAD.sup.+]-dependent deacetylase, was significantly increased by CA. Considering the above results, we hypothesized that SIRT1 may play important roles in the protective effects of CA in injury induced by [H.sub.2][O.sub.2]. As expected, SIRT1 suppression by Ex527 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) and siRNA-mediated SIRT1 silencing (si-SIRT1) significantly aggravated the [H.sub.2][O.sub.2]-induced increased level of cleaved caspase-3 but greatly reduced the decreased expression of MnSOD and Bcl-xL. Furthermore, the positive regulatory effect of CA was inhibited by si-SIRT1. Collectively, the present study indicated that CA can alleviate [H.sub.2][O.sub.2]-induced hepatocyte damage through the SIRT1 pathway. Key words: carnosic acid, SIRT1, hydrogen peroxide, reactive oxygen species, HepG2 cells. On rapporte que l'acide carnosique (AC), trouve dans le romarin, possede des proprietes antioxydantes et antiadipogenes. Les auteurs examinent ici le mecanisme moleculaire par lequel l'AC inhibe le dommage induit par le peroxyde d'hydrogene ([H.sub.2][O.sub.2]) chez les cellules HepG2. Les cellules ont ete pretraitees avec 2,5-10 µmol/L d'AC pendant 2 h puis exposees a 3 mmol/L de [H.sub.2][O.sub.2] pendant 4 h additionnelles. L'AC accroissait la viabilite cellulaire en fonction de sa concentration et diminuait l'activite de la lactate deshydrogenase. Le pretraitement a l'AC contrecarrait completement l'inhibition de l'expression de la superoxyde dismutase a manganese (MnSOD) et de Bcl-xL (<< B-cell lymphoma-extra large >>), et il reduisait l'activite du glutathion stimulee par le [H.sub.2][O.sub.2], alors qu'il renversait l'accumulation d'especes reactives d'oxygene et l'augmentation de caspase-3 clivee. Fait important, la sirtuin1 (SIRT1), une deacetylase dependante du [NAD.sup.+], etait significativement accrue par l'AC. Considerant les resultats decrits plus haut, les auteurs ont pose l'hypothese que SIRT1 puisse jouer un role important dans les effets protecteurs de l'AC contre le dommage cause par le [H.sub.2][O.sub.2]. Comme prevu, la suppression de SIRT1 par Ex527 (<< 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide>>) et un ARNic-SIRT1 augmentait davantage et de maniere significative les niveaux de caspase-3 clivee induits par le [H.sub.2][O.sub.2], mais attenuait fortement la diminution d'expression de MnSOD et de Bcl-xL. De plus, l'effet regulateur positif de l'AC etait inhibe par un ARNic-SIRT1. Dans son ensemble, l'etude presente a indique que l'AC peut attenuer le dommage induit aux hepatocytes par le [H.sub.2][O.sub.2] par l'intermediaire de la voie de SIRT1. [Traduit par la Redaction] Mots-cles: acide carnosique, SIRT1, peroxyde d'hydrogene, especes reactives d'oxygene, cellules HepG2., Introduction Reactive oxygen species (ROS) are produced during normal cellular metabolism and accumulated dramatically from environmental stress (Zhao et al. 2006). To scavenge these ROS, cells have intrinsic antioxidant mechanisms, [...]