Mesencephalic astrocyte-derived neurotrophic factor protects against paracetamol -induced liver injury by inhibiting PERK-ATF4-CHOP signaling pathway.
Biochem Biophys Res Commun
; 602: 163-169, 2022 04 30.
Article
em En
| MEDLINE
| ID: mdl-35278889
ABSTRACT
Paracetamol (APAP), an over-the-counter drug, is normally safe within the therapeutic dose range but can cause irreversible liver damage after an overdose. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress protein and plays a crucial role in metabolic disease. However, the role of MANF in APAP-induced acute hepatotoxicity is still unknown. We used hepatocyte-specific MANF-knockout mice and hepatocyte-specific MANF transgenic mice to investigate the role of hepatocyte-derived MANF in APAP-induced acute liver injury. MANF deficiency was associated with a decreased expression of detoxification enzymes, aggravated glutathione depletion and apoptosis in hepatocytes. Mechanistically, MANF knockout significantly increased PERK-eIF2α-ATF4-CHOP signaling pathway. Blockade of PERK abolished MANF deficiency-over-induced hepatotoxicity after APAP administration. Conversely, hepatocyte-specific MANF overexpression attenuated APAP-induced hepatotoxicity by downregulating the PERK-eIF2α-ATF4-CHOP signaling pathway. Thus, hepatocyte-derived MANF may play a protective role in APAP-induced hepatotoxicity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença Hepática Crônica Induzida por Substâncias e Drogas
/
Acetaminofen
Limite:
Animals
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China