Dataset Information

Interaction between PSMD10 and GRP78 accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine.

ABSTRACT:

Background

The liver plays an important role in production and metabolism of homocysteine (Hcy), which has been reported to be involved in liver injury. In our previous work, we confirm that Hcy can induce liver injury by activating endoplasmic reticulum (ER) stress. However, the underlying mechanisms remain largely unknown.

Results

In present study, we established the Hcy-induced liver injury model by feeding cbs^+/- mice with high methionine diet, and found that a considerable mass of disordered arrangement of hepatocytes and enlarged space between hepatocytes were frequently occurred in the liver of cbs^+/- mice, accompanied with elevated expression levels of apoptosis-related proteins. In addition, Hcy could activate ER stress both in cbs^+/- mice and hepatocytes. Mechanistically, Hcy promoted the expression levels of proteasome 26S subunit non-ATPase 10 (PSMD10) in hepatocytes; and the expression of ER stress indicators and apoptosis-associated proteins were significantly suppressed when PSMD10 was silenced in hepatocytes under Hcy treatment. Moreover, bioinformatics analysis and luciferase reporter assay demonstrated that PSMD10 was a target gene of miR-212-5p. Consistently, miR-212-5p overexpression could inhibit ER stress-mediated apoptosis of hepatocytes under Hcy treatment. With the help of co-immunoprecipitation assay, we identified that the interaction between PSMD10 and GRP78 accelerated ER stress-mediated hepatic apoptosis induced by Hcy.

Conclusions

Our findings indicate that miR-212-5p directly targets PSMD10 and subsequently activates ER stress to promote Hcy-induced apoptosis of hepatocytes. We propose that endogenous PSMD10 physically interacts with GRP78 to regulate ER stress. Our study may provide the therapeutic target for the liver injury induced by Hcy.

SUBMITTER: Xiao K

PROVIDER: S-EPMC8527788 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Interaction between PSMD10 and GRP78 accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine.

Xiao Kun K Ma Shengchao S Xu Long L Ding Ning N Zhang Hui H Xie Lin L Xu Lingbo L Jiao Yun Y Zhang Huiping H Jiang Yideng Y

Gut pathogens 20211019 1

<h4>Background</h4>The liver plays an important role in production and metabolism of homocysteine (Hcy), which has been reported to be involved in liver injury. In our previous work, we confirm that Hcy can induce liver injury by activating endoplasmic reticulum (ER) stress. However, the underlying mechanisms remain largely unknown.<h4>Results</h4>In present study, we established the Hcy-induced liver injury model by feeding cbs<sup>+/-</sup> mice with high methionine diet, and found that a cons ...[more]

PMID: 34666830

Similar Datasets

Project description:ObjectiveHepatic ischemia-reperfusion injury (HIRI) frequently occurs as a complication in liver surgeries, which significantly impacting patient outcomes. Sinensetin (SEN) is a plant-derived polymethoxylated flavone with anti-inflammatory and anti-oxidative activities. However, the hepatoprotective effect of sinensetin in HIRI pathogenesis have not been fully explored.MethodsWe constructed the HIRI model in mice, with blood and liver samples collected at 6 and 24 h after reperfusion to evaluate liver injury. We also evaluated the protective effect of sinensetin in mice liver I/R injury through histopathological observation, enzyme activity, immunofluorescence, Western blot, molecular docking, and molecular pharmacology experiments.ResultsIn our study, we have successfully established the mouse HIRI injury model, and the liver function indicators such as ALT, AST and LDH were significantly increased in the HIRI model group, while SEN pretreatment could lead to a significant decrease in these enzymatic activities, especially perfusion at 6 h. In addition, hepatocytic necrosis and lipid deposition were significantly improved under SEN pretreatment conditions compared to the HIRI group alone. Meanwhile, HIRI can significantly increase the expression of genes related to liver injury and inflammation, while SEN pretreatment can lead to a concentration-dependent decrease in these genes. Besides, the level of liver apoptosis and apoptosis-related genes such as BAX and Bcl-2 were significantly reduced especially in the high concentration SEN pretreatment group, and antioxidant enzyme activities such as CAT and GSH-Px also showed similar changes. Moreover, the HIRI model and SEN pretreatment could lead to dynamic changes in key genes involved in endoplasmic reticulum (ER) stress signaling, while the expression and distribution of GRP78 and CHOP proteins in liver cells also showed significant decrease in HIRI + L-SEN and HIRI + H-SEN groups. Molecular docking simulation showed theoretical binding between SEN-GRP78 and SEN-IRE1α in three-dimensional structures. Ultimately, the use of 4-PBA to pharmacologically inhibit ER stress may substantially reduce liver damage caused by HIRI in mice.ConclusionTaken together, our results suggested that sinensetin could alleviate HIRI injury through suppressing GRP78/CHOP-mediated ER stress, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury in clinical practice.

Dataset Information

Interaction between PSMD10 and GRP78 accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine.

Background

Results

Conclusions

Publications

Interaction between PSMD10 and GRP78 accelerates endoplasmic reticulum stress-mediated hepatic apoptosis induced by homocysteine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets