Abstract
Hepatic sinusoidal obstruction syndrome (HSOS) is a death-dealing liver disease with a fatality rate of up to 67%. In the study present, we explored the efficacy of andrographolide (Andro), a diterpene lactone from Andrographis Herba, in ameliorating the monocrotaline (MCT)-induced HSOS and the underlying mechanism. The alleviation of Andro on MCT-induced rats HSOS was proved by biochemical index detection, electron microscope observation, and liver histological evaluation. Detection of hepatic ATP content, mitochondrial DNA (mtDNA) copy number, and protein expression of nuclear respiratory factor-1 (NRF1) and peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A) demonstrated that Andro strengthened mitochondrial biogenesis in livers from MCT-treated rats. Chromatin immunoprecipitation assay exhibited that Andro enhanced the occupation of nuclear factor erythroid 2-related factor 2 (NFE2L2, also known as NRF2) in the promoter regions of both PPARGC1A and NRF1. Andro also activated the NRF2-dependent anti-oxidative response and alleviated liver oxidative injury. In Nrf2 knock-out mice, MCT induced more severe liver damage, and Andro showed no alleviation in it. Furthermore, the Andro-activated mitochondrial biogenesis and anti-oxidative response were reduced in Nrf2 knock-out mice. Contrastingly, knocking out Kelch-like ECH-associated protein 1 (Keap1), a NRF2 repressor, reduced MCT-induced liver damage. Results from co-immunoprecipitation, molecular docking analysis, biotin-Andro pull-down, cellular thermal shift assay, and surface plasmon resonance assay showed that Andro hindered the NRF2-KEAP1 interaction via directly binding to KEAP1. In conclusion, our results revealed that NRF2-dependent liver mitochondrial biogenesis and anti-oxidative response were essential for the Andro-provided alleviation of the MCT-induced HSOS.
Graphical abstract
Graphical Headlights:
1. Andro alleviated MCT-induced HSOS via activating antioxidative response and promoting mitochondrial biogenesis.
2. Andro-activated antioxidative response and mitochondrial biogenesis were NRF2-dependent.
3. Andro activated NRF2 via binding to KEAP1.
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Data availability
Data and materials used and/or analyzed during the current study are available from the corresponding authors on reasonable request.
Abbreviations
- ALT/AST:
-
Alanine/aspartate aminotransferase
- Andro:
-
Andrographolide
- ARE:
-
Antioxidant-responsive element
- ATP:
-
Adenosine triphosphate
- CETSA:
-
Cellular thermal shift assay
- ChIP:
-
Chromatin immunoprecipitation
- CoIP:
-
Co-immunoprecipitation
- COX4I1:
-
Cytochrome c oxidase subunit 4I1
- CYCS:
-
Cytochrome C
- DAPI:
-
4′,6-Diamidino-2-phenylindole
- GCLC:
-
Catalytic subunit of glutamate-cysteine ligase
- GCLM:
-
Modifier subunit of glutamate-cysteine ligase
- GSR:
-
Glutathione-disulfide reductase
- HHSEC:
-
Human hepatic sinusoidal endothelial cell
- HO-1:
-
Hemeoxygenase1
- HSCT:
-
Hematopoietic stem cell transplantation
- HSOS:
-
Hepatic sinusoidal obstruction syndrome
- H2DCFDA:
-
2′-7′-Dichlorodihydro-fluorescein diacetate
- KEAP1:
-
Kelch-like ECH-associated protein 1
- LSECs:
-
Liver sinusoidal endothelial cells
- MCT:
-
Monocrotaline
- MDA:
-
Malondialdehyde
- MMP9:
-
Matrix metalloproteinase 9
- mtDNA:
-
Mitochondrial DNA
- nDNA:
-
Nuclear DNA
- NRF1:
-
Nuclear respiratory factor 1
- NRF2:
-
Nuclear factor erythroid 2-related factor 2
- PBS:
-
Phosphate-buffered saline
- PPARGC1A:
-
Peroxisome proliferator–activated receptor gamma coactivator 1α
- ROS:
-
Reactive oxygen species
- SEM:
-
Standard error of the mean
- SOD:
-
Superoxide dismutase
- TFAM:
-
Mitochondrial transcription factor A
- TOM20:
-
Outer mitochondrial membrane 20
- TRX1:
-
Thioredoxin 1
- TRXR1:
-
Thioredoxin reductase 1
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Funding
This work was financially supported by the “Young Qihuang Scholar” and the Shanghai Excellent Academic Leaders Program (23XD1404000) for Lili Ji, the National Natural Science Foundation of China (82104509), and the Shanghai Pujiang Program (22PJ1412900) for Zhenlin Huang.
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Zhenlin Huang and Lili Ji conceptualized this study and designed the research. Zhenlin Huang, Zeqi Wu, Jingnan Zhang, Keke Wang, Qing Zhao, Minwei Chen, Shihao Yan, and Qian Guo conducted the experiments and analyzed the data. Zhenlin Huang drafted the manuscript. Yun Ma and Lili Ji revised the manuscript. All authors have read and approved the final manuscript.
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Huang, Z., Wu, Z., Zhang, J. et al. Andrographolide attenuated MCT-induced HSOS via regulating NRF2-initiated mitochondrial biogenesis and antioxidant response. Cell Biol Toxicol 39, 3269–3285 (2023). https://doi.org/10.1007/s10565-023-09832-7
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DOI: https://doi.org/10.1007/s10565-023-09832-7