SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation

Autor: Yajie Wen, Jiahong Sun, Panpan Chen, Wenzhou Li, Tingying Jiao, Huichang Bi, Yanying Zhou, Yixin Chen, Lihuan Guan, Pan Chen, Fan Xiaomei, Yiming Jiang, Min Huang
Jazyk: angličtina
Rok vydání: 2020
Předmět:
GSTα
glutathianone S-transferase α
NAPQI
N-acetyl p-benzoquinone imine
AST
aspartate aminotransferase
Pharmacology
medicine.disease_cause
BrdU
bromodeoxyuridine
CDK4
cyclin-dependent kinase 4
0302 clinical medicine
AAV
adeno-associated virus
ECL
electrochemiluminescence
GSTμ
glutathione S-transferase μ
GSH
glutathione
General Pharmacology
Toxicology and Pharmaceutics
HO-1
heme oxygenase-1
Liver injury
0303 health sciences
Gene knockdown
biology
LDH
lactate dehydrogenase
Chemistry
CYP450
cytochromes P450
digestive
oral
and skin physiology
SIRT6
sirtuin 6
medicine.anatomical_structure
030220 oncology & carcinogenesis
Hepatocyte
Sirtuin
NRF2
nuclear factor erythroid 2-related factor 2
KEAP1
Kelch-like ECH-associated protein 1
Original Article
SIRT6
DNA damage
APAP
acetaminophen
ARE
antioxidant response element
NRF2
ALT
serum alanine aminotransferase
03 medical and health sciences
H3K9ac
histone H3 Nε-acetyl-lysines 9
CCK-8
cell counting kit-8
ROS
reactive oxygen species
ALF
acute liver failure
Dox
doxorubicin
H3K56ac
histone H3 Nε-acetyl-lysines 56
medicine
Viability assay
030304 developmental biology
Acetaminophen
P53
CCND1
cyclin D1
lcsh:RM1-950
Hepatotoxicity
medicine.disease
BCA
bicinchoninic acid
lcsh:Therapeutics. Pharmacology
DCF
dichlorofluorescein
siRNA
small interfering RNA
biology.protein
H&E
hematoxylin and eosin
CCNA1
cyclin A1
NQO1
NAD(P)H quinone dehydrogenase 1
Co-IP
co-immunoprecipitation
Oxidative stress
Zdroj: Acta Pharmaceutica Sinica. B
Acta Pharmaceutica Sinica B, Vol 11, Iss 1, Pp 89-99 (2021)
ISSN: 2211-3843
2211-3835
Popis: Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively. Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress, inhibited cell viability and proliferation, and downregulated CCNA1, CCND1 and CKD4 protein levels. Sirt6 knockdown significantly prevented APAP-induced NRF2 activation, reduced the transcriptional activities of GSTμ and NQO1 and the mRNA levels of Nrf2, Ho-1, Gstα and Gstμ. Furthermore, SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation (Co-IP) assay. Additionally, the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6-dependent. The Sirt6 mRNA was significantly down-regulated in P53−/− mice. P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6. Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation, and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.
Graphical abstract Image 1Sirtuin 6 as a transcriptional coactivator of P53 and nuclear factor erythroid 2-related factor 2 (NRF2) protects against acetaminophen-induced hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation.
Databáze: OpenAIRE
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