Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells
Emodin, an emerging mycotoxin, is known to be hepatotoxic, but its mechanism remains unclear. We hypothesized that emodin could induce endoplasmic reticulum (ER) stress through the inositol-requiring enzyme 1 alpha (IRE1α)–X-box-binding protein 1 (XBP1) pathway and apoptosis, which are closely corre...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-07-01
|
| Series: | Toxins |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6651/15/7/455 |
| _version_ | 1797587274418880512 |
|---|---|
| author | Su Been Park Gun Hee Cho Young Eun Park Hyang Sook Chun |
| author_facet | Su Been Park Gun Hee Cho Young Eun Park Hyang Sook Chun |
| author_sort | Su Been Park |
| collection | DOAJ |
| description | Emodin, an emerging mycotoxin, is known to be hepatotoxic, but its mechanism remains unclear. We hypothesized that emodin could induce endoplasmic reticulum (ER) stress through the inositol-requiring enzyme 1 alpha (IRE1α)–X-box-binding protein 1 (XBP1) pathway and apoptosis, which are closely correlated and contribute to hepatotoxicity. To test this hypothesis, a novel IRE1α inhibitor, STF-083010, was used. An MTT assay was used to evaluate metabolic activity, and quantitative PCR and western blotting were used to investigate the gene and protein expression of ER stress or apoptosis-related markers. Apoptosis was evaluated with flow cytometry. Results showed that emodin induced cytotoxicity in a dose-dependent manner in HepG2 cells and upregulated the expression of binding immunoglobulin protein (BiP), C/EBP homologous protein (CHOP), IRE1α, spliced XBP1, the B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio, and cleaved caspase-3. Cotreatment with emodin and STF-083010 led to the downregulation of BiP and upregulation of CHOP, the Bax/Bcl-2 ratio, and cleaved caspase-3 compared with single treatment with emodin. Furthermore, the apoptosis rate was increased in a dose-dependent manner with emodin treatment. Thus, emodin induced ER stress in HepG2 cells by activating the IRE1α–XBP1 axis and induced apoptosis, indicating that emodin can cause hepatotoxicity. |
| first_indexed | 2024-03-11T00:34:49Z |
| format | Article |
| id | doaj.art-000809cd40d04bf6b7ac42143c533575 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-11T00:34:49Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-000809cd40d04bf6b7ac42143c5335752023-11-18T21:38:26ZengMDPI AGToxins2072-66512023-07-0115745510.3390/toxins15070455Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 CellsSu Been Park0Gun Hee Cho1Young Eun Park2Hyang Sook Chun3School of Food Science and Technology, Chung-Ang University, Anseong 17546, Republic of KoreaSchool of Food Science and Technology, Chung-Ang University, Anseong 17546, Republic of KoreaSchool of Food Science and Technology, Chung-Ang University, Anseong 17546, Republic of KoreaSchool of Food Science and Technology, Chung-Ang University, Anseong 17546, Republic of KoreaEmodin, an emerging mycotoxin, is known to be hepatotoxic, but its mechanism remains unclear. We hypothesized that emodin could induce endoplasmic reticulum (ER) stress through the inositol-requiring enzyme 1 alpha (IRE1α)–X-box-binding protein 1 (XBP1) pathway and apoptosis, which are closely correlated and contribute to hepatotoxicity. To test this hypothesis, a novel IRE1α inhibitor, STF-083010, was used. An MTT assay was used to evaluate metabolic activity, and quantitative PCR and western blotting were used to investigate the gene and protein expression of ER stress or apoptosis-related markers. Apoptosis was evaluated with flow cytometry. Results showed that emodin induced cytotoxicity in a dose-dependent manner in HepG2 cells and upregulated the expression of binding immunoglobulin protein (BiP), C/EBP homologous protein (CHOP), IRE1α, spliced XBP1, the B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio, and cleaved caspase-3. Cotreatment with emodin and STF-083010 led to the downregulation of BiP and upregulation of CHOP, the Bax/Bcl-2 ratio, and cleaved caspase-3 compared with single treatment with emodin. Furthermore, the apoptosis rate was increased in a dose-dependent manner with emodin treatment. Thus, emodin induced ER stress in HepG2 cells by activating the IRE1α–XBP1 axis and induced apoptosis, indicating that emodin can cause hepatotoxicity.https://www.mdpi.com/2072-6651/15/7/455emodinmycotoxinER stressapoptosisHepG2 cellshepatotoxicity |
| spellingShingle | Su Been Park Gun Hee Cho Young Eun Park Hyang Sook Chun Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells Toxins emodin mycotoxin ER stress apoptosis HepG2 cells hepatotoxicity |
| title | Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells |
| title_full | Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells |
| title_fullStr | Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells |
| title_full_unstemmed | Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells |
| title_short | Emodin, an Emerging Mycotoxin, Induces Endoplasmic Reticulum Stress-Related Hepatotoxicity through IRE1α–XBP1 Axis in HepG2 Cells |
| title_sort | emodin an emerging mycotoxin induces endoplasmic reticulum stress related hepatotoxicity through ire1α xbp1 axis in hepg2 cells |
| topic | emodin mycotoxin ER stress apoptosis HepG2 cells hepatotoxicity |
| url | https://www.mdpi.com/2072-6651/15/7/455 |
| work_keys_str_mv | AT subeenpark emodinanemergingmycotoxininducesendoplasmicreticulumstressrelatedhepatotoxicitythroughire1axbp1axisinhepg2cells AT gunheecho emodinanemergingmycotoxininducesendoplasmicreticulumstressrelatedhepatotoxicitythroughire1axbp1axisinhepg2cells AT youngeunpark emodinanemergingmycotoxininducesendoplasmicreticulumstressrelatedhepatotoxicitythroughire1axbp1axisinhepg2cells AT hyangsookchun emodinanemergingmycotoxininducesendoplasmicreticulumstressrelatedhepatotoxicitythroughire1axbp1axisinhepg2cells |