Intermittent hypoxia aggravates non-alcoholic fatty liver disease via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway.
Life Sci
; 285: 119963, 2021 Nov 15.
Article
in En
| MEDLINE
| ID: mdl-34536498
ABSTRACT
AIMS:
Hepatocyte necroptosis is a critical event in the progression of non-alcoholic fatty liver disease (NAFLD). Obstructive sleep apnea hypopnea syndrome (OSAHS) and chronic intermittent hypoxia (CIH) may be linked with the pathogenesis and the severity of NAFLD. However, the potential role of necroptosis in OSAHS-associated NAFLD has not been evaluated. The present study investigated whether IH could affect NAFLD progression through promoting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis, oxidative stress, and inflammatory response, and further elucidated the underlying molecular mechanisms. MAINMETHODS:
LO2 cells were treated with palmitic acid (PA) and subjected to IH, and necroptosis, oxidative stress, and inflammation were assessed. The high-fat choline-deficient (HFCD)-fed mouse model was also used to assess the effects of CIH in experimental NAFLD in vivo. KEYFINDINGS:
In this study, we found that RIPK3-mediated necroptosis was activated both in the PA plus IH-treated LO2 cells and liver of HFCD/CIH mice, and which could trigger oxidative stress and inflammatory response by decreasing Nrf2 and increasing p-P65. RIPK3 downregulation significantly reduced hepatocyte necroptosis, and ameliorated oxidative stress and inflammation through modulating Nrf2/NFκB pathway in vitro and vivo. Similarly, pretreatment with TBHQ, an activator of Nrf2, effectively blocked the generation of oxidative productions and inflammatory cytokines. In addition, RIPK3 inhibitor GSK-872 or TBHQ administration obviously alleviated hepatic injury, including histology, transaminase activities, and triglyceride contents in vivo.SIGNIFICANCE:
IH aggravates NAFLD via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway, and which should be considered as a potential therapeutic strategy for the treatment of NAFLD with OSASH.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
NF-kappa B
/
Sleep Apnea, Obstructive
/
NF-E2-Related Factor 2
/
Receptor-Interacting Protein Serine-Threonine Kinases
/
Non-alcoholic Fatty Liver Disease
/
Necroptosis
/
Hypoxia
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Life Sci
Year:
2021
Document type:
Article
Affiliation country:
China
Publication country:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
/
PAISES BAJOS
/
THE NETHERLANDS