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Lipotoxicity and unresolved oxidative stress are key drivers of metabolic inflammation in nonalcoholic steatohepatitis (NASH). cAMP-response element binding protein H(CREBH) is a liver-specific transcription factor and regulates the glucose and lipid metabolism of NASH. However, its role in mitochondrial oxidative stress and its association with sirtuin 3 (SIRT3), a master regulator of deacetylation for mitochondrial proteins, remains elusive. In this study, AML-12 cells were treated with palmitic acid to imitate the pathological changes of NASH in vitro and 8-week-old male C57BL/6J mice were fed with a high-fat (HF) diet or a methionine-choline-deficient (MCD) diet to build the widely accepted in vivo model of NASH. We found that lipid overload induced mitochondrial oxidative stress and stimulated the expression of CREBH and SIRT3. CREBH overexpression alleviated the mitochondrial oxidative stress. Moreover, CREBH promoted SIRT3 expression, which regulated the deacetylation of manganese superoxide dismutase (MnSOD) and inhibited NOD-Like Receptor Pyrin Domain Containing 3 (Nlrp3) inflammasome activation whereas suppression of SIRT3 damaged the protecting ability of CREBH in mitochondrial oxidative stress. CREBH knockout mice were highly susceptible to HF and MCD diet-induced NASH with more severe oxidative stress. Collectively, our results firstly provided the support that CREBH could serve as a protective factor in the progression of NASH by regulating the acetylation of MnSOD and the activation of Nlrp3 inflammasome through SIRT3. These results suggest that CREBH might be a valuable therapeutic candidate for NASH. [Display omitted] • Lipid overload induced mitochondrial oxidative stress and stimulated the expression of CREBH and SIRT3. • CREBH overexpression promoted SIRT3 expression, regulating MnSOD acetylation and inhibiting Nlrp3 inflammasome activation. • Suppression of SIRT3 damaged the protecting ability of CREBH against mitochondrial oxidative stress in hepatocytes. • This study identifies a novel mechanism of CREBH in the development of NASH, providing a valuable therapeutic candidate for NASH. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that circular RNAs (circRNAs) are involved in the development of various liver diseases. However, the regulatory role of circRNAs in nonalcoholic steatohepatitis (NASH) has not been fully elucidated. In the present study, the circRNA profiles in a NASH mouse model were investigated, and their functions in NASH were predicted using bioinformatics analysis, with the aim of providing novel clues for delineating the mechanisms of action. A NASH mouse model was established by feeding mice with a methionine and choline-deficient diet. The liver circRNA profile was screened using a circRNA microarray, and the differentially expressed circRNAs were verified by reverse transcription-quantitative polymerase chain reaction. Subsequently, circRNA-microRNA (miRNA) interactions were predicted. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the biological functions of host linear transcripts of circRNA. A total of 450 circRNAs were revealed to be dysregulated, with 298 circRNAs upregulated and 152 circRNAs downregulated in the NASH model mice. circRNA_29981 was identified as a significantly differentially expressed circRNA. The results from the circRNA-miRNA pathway interaction analysis revealed that circRNA_29981 was a potential regulator of hepatic stellate cell activation. The host linear transcripts were also analyzed, and the top 10 enriched GO entries and KEGG pathways were annotated. These findings suggested that circRNAs may be important regulators of NASH. Taken together, the results of the present study demonstrated that the circRNA profile in NASH may provide potential candidates for future studies aimed at elucidating the pathogenic mechanism(s) involved in the disease. [ABSTRACT FROM AUTHOR]