LONP1 ameliorates liver injury and improves gluconeogenesis dysfunction in acute-on-chronic liver failure / 中华医学杂志(英文版)

BACKGROUND@#Acute-on-chronic liver failure (ACLF) is a severe liver disease with complex pathogenesis. Clinical hypoglycemia is common in patients with ACLF and often predicts a worse prognosis. Accumulating evidence suggests that glucose metabolic disturbance, especially gluconeogenesis dysfunction, plays a critical role in the disease progression of ACLF. Lon protease-1 (LONP1) is a novel mediator of energy and glucose metabolism. However, whether gluconeogenesis is a potential mechanism through which LONP1 modulates ACLF remains unknown.@*METHODS@#In this study, we collected liver tissues from ACLF patients, established an ACLF mouse model with carbon tetrachloride (CCl 4 ), lipopolysaccharide (LPS), and D-galactose (D-gal), and constructed an in vitro hypoxia and hyperammonemia-triggered hepatocyte injury model. LONP1 overexpression and knockdown adenovirus were used to assess the protective effect of LONP1 on liver injury and gluconeogenesis regulation. Liver histopathology, biochemical index, mitochondrial morphology, cell viability and apoptosis, and the expression and activity of key gluconeogenic enzymes were detected to explore the underlying protective mechanisms of LONP1 in ACLF.@*RESULTS@#We found that LONP1 and the expressions of gluconeogenic enzymes were downregulated in clinical ACLF liver tissues. Furthermore, LONP1 overexpression remarkably attenuated liver injury, which was characterized by improved liver histopathological lesions and decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ACLF mice. Moreover, mitochondrial morphology was improved upon overexpression of LONP1. Meanwhile, the expression and activity of the key gluconeogenic enzymes were restored by LONP1 overexpression. Similarly, the hepatoprotective effect was also observed in the hepatocyte injury model, as evidenced by improved cell viability, reduced cell apoptosis, and improved gluconeogenesis level and activity, while LONP1 knockdown worsened liver injury and gluconeogenesis disorders.@*CONCLUSION@#We demonstrated that gluconeogenesis dysfunction exists in ACLF, and LONP1 could ameliorate liver injury and improve gluconeogenic dysfunction, which would provide a promising therapeutic target for patients with ACLF.

E ffect of deacetylase inhibitor VPA on polarization of macrophages / 中国免疫学杂志

Objective:By analyzing the effect of deacetylase inhibitors on macrophage polarization process of histone modification,and the influence of the process of macrophage polarization ,analysis deacetylase inhibitors whether have the effect on the activity of the macrophage polarization by altered histone modification of macrophages , in order to provide a new perspective for the treatment of autoimmune diseases .Methods:Using lipopolysaccharide ( LPS) and interferon-γ( IFN-γ) to stimulate J774.1 cells for 24 h,and interleukin-4 ( IL-4 ) to stimulate J774.1 cells for 24 h.And 2 mmol/L valproic acid ( VPA ) was added in the induction process.Collecting J774.1 cells,fluorescent quantitation PCR assay and ELISA assay was used for the detection of specific markers of gene expression in macrophage polarization , flow cytometry and immunofluorescence assay for the detection of histone modifications.Results:J774.1 cells were polarized into M1 macrophages which were stimulated by LPS and IFN-γfor 24 h;and also J774.1 cells were polarized into M2 macrophages which were stimulated by IL-4 for 24 h.The degree of acetylation of H 3K9 for M1 phenotype was increased after VPA treatment , the expression of interleukin-6 (IL-6 ) , inducible nitric oxide synthase ( iNOS ) , and chemotactic factor(CCL-2) was decreased,and the expression of CD86 was increased.The degree of acetylation of H3K9 for M1 phenotype was also increased after VPA treatment ,and also the expression of Arginase,Fizz-1,mannose receptor(CD 206) and Ym1 were increased.Conclusion:The polarization state of the macrophages and histone modification had a certain relevance .VPA could induce the transformation of M1 phenotype to M2 phenotype in the induction system of the M1 macrophages,however,the expression of specific genes in M1 phenotype was inhibited in the induction system of the M 2 macrophages.