Prolyl endopeptidase disruption reduces hepatic inflammation and oxidative stress in methionine-choline-deficient diet-induced steatohepatitis

Prolyl endopeptidase (PREP) is a serine endopeptidase widely distributed in the body, and accumulated evidence suggests that PREP participates in inflammation and oxidative stress. Here, we explored the effect of PREP gene disruption on hepatic inflammation and oxidative stress status in a methionin...

Full description

Saved in:
Bibliographic Details
Published in:Life sciences (1973) 2021-04, Vol.270, p.119131-119131, Article 119131
Main Authors: Zhang, Jianbin, Jiang, Daixi, Lin, Shuangzhe, Cheng, Yuqing, Pan, Jiaxing, Ding, Wenjin, Chen, Yuanwen, Fan, Jiangao
Format: Article
Language:English
Subjects:
Animals
Choline
Choline - metabolism
Choline Deficiency - complications
Cytokines
Cytokines - metabolism
Diet
Disruption
Downstream effects
Endopeptidase
Enzyme-linked immunosorbent assay
Fatty Liver - drug therapy
Fatty Liver - metabolism
Gene disruption
Hep G2 Cells
Hepatocellular carcinoma
Humans
Immunoblotting
Inflammation
Inflammation - metabolism
Liver
Liver - metabolism
Male
Methionine
Methionine - deficiency
Methionine - metabolism
Mice
Mice, Inbred C57BL
NASH
NF-kappa B - metabolism
Nutrient deficiency
Oxidative stress
Oxidative Stress - drug effects
p53 Protein
Palmitic acid
PREP gene disruption
Prolyl endopeptidase
Prolyl oligopeptidase
Prolyl Oligopeptidases - genetics
Prolyl Oligopeptidases - metabolism
Prolyl Oligopeptidases - physiology
Serine
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Prolyl endopeptidase (PREP) is a serine endopeptidase widely distributed in the body, and accumulated evidence suggests that PREP participates in inflammation and oxidative stress. Here, we explored the effect of PREP gene disruption on hepatic inflammation and oxidative stress status in a methionine-choline-deficient (MCD)-induced nonalcoholic steatohepatitis (NASH) model. PREP gene disruption (PREPgt) mice and wild-type (WT) littermates were placed on a control or an MCD diet for 4 weeks, respectively. The liver histopathological analysis and the number of inflammatory cells were determined by hematoxylin-eosin (HE) and immunohistochemical staining. Inflammation-associated genes and cytokine levels in liver tissue were evaluated by quantitative PCR and ELISA. The levels of P53, Sesn2, Nrf2, HO-1, and oxidative stress indicators in mice and the palmitic acid (PA)-treated human hepatocellular carcinoma cells (HepG2) were examined by immunoblotting and commercially available kits, respectively. We found that PREP expression was upregulated in the MCD-induced NASH model. In addition, PREP disruption alleviated MCD-induced hepatic inflammation accompanied by diminished infiltration of inflammatory cells and secretion of inflammatory mediators. More importantly, the results of this study indicate that targeting PREP can improve oxidative stress status in the liver of MCD-diet mice and PA-exposed HepG2 cells. The effect is most likely mediated by the activation of P53 and its downstream signaling pathways (Sesn2/Nrf2/HO-1). Our results showed that PREP disruption (or inhibition) could decrease oxidative stress and inflammation and improve liver function, indicating that targeting PREP might be a new potential therapeutic option for NAFLD/NASH.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2021.119131