RESUMO
Nonalcoholic steatohepatitis (NASH) is a global public health challenge. Overwhelmed oxidative stress and impaired autophagy play an important role in the progression of NASH. Chemerin is an adipokine that has attracted much attention in inflammation and metabolic diseases. This study aimed to examine the effects of chemerin in NASH and its association with oxidative stress and autophagy. In this study, chemerin was found to significantly ameliorate high-fat diet (HFD) induced NASH, marked by decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α), decreased insulin resistance (IR) and leptin resistance (LR), and improved liver lesions. Besides, chemerin prevented enhanced oxidative stress in NASH mice by regulating the antioxidant defense system (MDA downregulation and upregulation of superoxide dismutase (SOD)). Moreover, chemerin contributed to the alleviation of NASH through autophagy activation (p62 downregulation, and upregulation of beclin-1 and LC3). Furthermore, these effects were related to increased phosphorylation of JAK2-STAT3 stimulated by chemerin, which could be inhibited by the CMKLR1 specific inhibitor α-NETA. In conclusion, excess chemerin highly probably ameliorated NASH by alleviating oxidative stress and promoting autophagy, the mechanism responsible for this process was related, at least in part, to the increased phosphorylation of JAK2-STAT3 stimulated by chemerin/CMKLR1. Rh-chemerin may represent promising therapeutic targets in the treatment of NASH.
Assuntos
Autofagia/genética , Quimiocinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Janus Quinase 2/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Transcrição STAT3/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Humanos , Resistência à Insulina/genética , Leptina/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND AND AIM: Myeloid-derived suppressor cells are a heterogeneous cell population that expand during several pathogenic conditions. However, their role in non-alcoholic steatohepatitis remains unclear. This study aimed to examine the systemic effects of myeloid-derived suppressor cells, to determine the role of Gr-1highLy6G+MDSCs and their correlation with the CXCL12/CXCR4 axis in non-alcoholic steatohepatitis. METHODS: We established a non-alcoholic steatohepatitis model and detected inflammatory factors IL-6, PGE2, and INF-γ, using an enzyme-linked immunosorbent assay. Proportions of lymphocyte subsets in peripheral blood, CD11b+Gr-1+myeloid-derived suppressor cells and its subsets in the blood, spleen, liver, and bone marrow were identified using flow cytometry. Adoptive transfer and depletion experiments for MDSCs were performed. Immunohistochemistry, migration assays, and in vivo experiments were used to analyze the role of CXCL12/CXCR4 in non-alcoholic steatohepatitis. RESULTS: The proportion of CD11b+Gr-1+MDSCs changed in the bone marrow, spleen, blood, and liver in the non-alcoholic steatohepatitis model. CD4+ and CD8+ T lymphocytes were significantly reduced in non-alcoholic steatohepatitis. Compared with control mice, a significant decrease in ALT and AST levels was observed in Gr-1highLy6G+MDSCs-treated model mice. The migration ability of AMD3100-treated MDSCs was significantly reduced, but was restored as CXCL12 levels increased. CXCL12 and CXCR4 protein levels increased significantly in the non-alcoholic steatohepatitis livers. CONCLUSIONS: Exogenous Gr-1highLy6G+MDSCs improved liver function during non-alcoholic steatohepatitis. The CXCR4/CXCL12 axis could be the key pathway mediating the attraction of myeloid-derived suppressor cells into the non-alcoholic steatohepatitis environment in mice.
RESUMO
INTRODUCTION AND AIM: Hepatocyte growth factor (HGF) has been shown to ameliorate liver inflammation and fibrosis; however, the mechanism underlying its effects in non-alcoholic steatohepatitis (NASH) is unclear. This study aimed to analyse the relationship between the JAK2-STAT3 signalling pathway and the ameliorating effect of HGF on NASH. MATERIAL AND METHODS: Mice were fed a high-fat diet (HFD) for 16 weeks, and then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess liver disease. The mRNA and protein levels of JAK2, STAT3, and c-Met were assessed by real-time PCR and western blotting, respectively. RESULTS: Serum ALT, AST, and TG levels were increased in NASH mice. Histological analysis showed different degrees of steatosis, inflammatory infiltrates, and fibrosis in HFD animals. Exogenous administration of recombinant human (rh) HGF via the tail vein for 14 days markedly decreased ALT and AST to levels lower than those in the control group. Compared with the levels in HFD mice, c-Met, p-c-Met, JAK2, p-JAK2, and p-STAT3 levels were increased in mice that were administered HGF (P < 0.05). Furthermore, silencing of HGF or blocking of its receptor c-Met affected JAK2 and STAT3 protein phosphorylation. CONCLUSIONS: Excess HGF highly probable improved NASH liver function. Combined with its ligand, c-Met, HGF may promote the phosphorylation of JAK2-STAT3 and inhibit inflammation in NASH. Therefore, it may be potentially useful treatment for NASH.