ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation

Abstract

Background: ENO3 expression is upregulated in Non-alcoholic fatty liver disease (NAFLD) patient tissues, demonstrated that ENO3 might play crucial roles in NAFLD. However, the mechanism of ENO3 in NAFLD remains unclear. Therefore, this study aimed to investigate the regulatory mechanism of ENO3 in the progression of non-alcoholic steatohepatitis (NASH) in vivo and vitro NASH model. Methods: In vivo and vitro NASH model were established by methionine-choline deficient (MCD)-diet feeding and high free fatty acid (HFFA) induction in L02 cells. Loss and gain function of ENO3 and GPX4 was performed to study the mechanism in NASH. Western blot was used to detect the expression of ENO3 and GPX4. Hematoxylin and eosin (H&E), picrosirius Red and Oil Red O staining was used to evaluate histopathology of liver in NASH model. Ferroptosis indicators were measured by assay kits according to the manufacturer's instructions.Results: NASH mouse model was successfully established induced by MCD diet with steatosis, inflammatory infiltration, ballooning and fibrosis observed in the liver tissue. The expression of ENO3 and GPX4 was significantly elevated while ferroptosis was inhibited in NASH mice and cell model. Upregulation of both ENO3 and GPX4 could promote the lipid accumulation in L02 cells. In addition, overexpressed ENO3 attenuated the status of ferroptosis.Conclusions: In the present study, we demonstrate that ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevating GPX4 expression and lipid accumulation. These findings provided solid foundation for the mechanism of ferroptosis on the progression of NASH regulated by ENO3, suggesting that ENO3 may be a potential therapeutic target for NASH.

Sperm Histone H3 Lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

“…2J, Lancaster p<0.05) with 129 overlapping with the F 1 WT HFD vs TG HFD males (p=0.06; Fig 2 x ). We identified 12 genes that showed transgenerational deregulated expression across the F 0 -F 2 , (WT HFD vs TG HFD), including Eno3 which has been implicated in glycogen storage [77, 78], Med23 which regulates insulin responsiveness [79], and Prmt1 an epigenetic regulator implicated in liver glucose metabolism [80–82]. The number of differentially expressed genes increased every generation in comparisons between the WT HFD and the TG HFD (F 0 =524, F 1 =961, F 2 = 2,141).…”

Targeting Mitochondrial ROS-Mediated Ferroptosis by Quercetin Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity

“…Ferroptosis is associated with the processes of lipid synthesis, storage and degradation ( Li and Li, 2020 ). Moreover, a previous study confirmed that GPX4 (a key regulator of ferroptosis) promotes lipid deposition in L-02 cells ( Lu et al, 2021 ). In this study, our data indicate that inhibition of ferroptosis by Fer-1 (an inhibitor of ferroptosis) and Que decreased both lipid peroxidation and lipid droplet accumulation.…”

Interaction between macrophages and ferroptosis

“…In terms of liver damage, targeting ferroptosis is found to have an effect on relieving or aggravating the symptoms, indicating the role of iron, lipid and amino acid metabolisms. Non-alcoholic fatty liver disease (NAFLD), like non-alcoholic steatohepatitis (NASH), can be promoted by iron accumulation, lipid peroxidation, GPX4 depletion and inflammatory initiation, which are main processes of ferroptosis [ 99 – 101 ]. After given ferroptosis inhibitors, such as liproxstatin-1 or ferrostatin-1, NASH is greatly alleviated [ 102 , 103 ].…”