Highlights
- •Low ClpP protein levels were found in the livers of mice with non-alcoholic steatohepatitis.
- •ClpP deficiency induced steatohepatitis and augmented high-calorie diet-induced steatohepatitis in C57BL/6J mice.
- •ClpP overexpression reduced hepatic steatosis, inflammation, and fibrosis in high-calorie diet-fed C57BL/6J mice.
- •A chemical activator of ClpP ameliorated high-calorie diet-induced steatohepatitis in C57BL/6J mice.
Background & Aims
Mitochondrial dysfunction is considered a pathogenic linker in the development of
non-alcoholic steatohepatitis (NASH). Inappropriate mitochondrial protein-quality
control, possibly induced by insufficiency of the mitochondrial matrix caseinolytic
protease P (ClpP), can potentially cause mitochondrial dysfunction. Herein, we aimed
to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether
supplementation of ClpP can ameliorate diet-induced NASH.
Methods
NASH was induced by a high-fat/high-fructose (HF/HFr) diet in C57BL/6J mice. Stress/inflammatory
signals were induced in mouse primary hepatocytes (MPHs) by treatment with palmitate/oleate
(PA/OA). ClpP levels in hepatocytes were reduced using the RNAi-mediated gene knockdown
technique but increased through the viral transduction of ClpP. ClpP activation was
induced by administering a chemical activator of ClpP.
Results
Hepatic ClpP protein levels in C57BL/6J mice fed a HF/HFr diet were lower than the
levels in those fed a normal chow diet. PA/OA treatment also decreased the ClpP protein
levels in MPHs. Overexpression or activation of ClpP reversed PA/OA-induced mitochondrial
dysfunction and stress/inflammatory signal activation in MPHs, whereas ClpP knockdown
induced mitochondrial dysfunction and stress/inflammatory signals in these cells.
On the other hand, ClpP overexpression or activation improved HF/HFr-induced NASH
characteristics such as hepatic steatosis, inflammation, fibrosis, and injury in the
C57BL/6J mice, whereas ClpP knockdown further augmented steatohepatitis in mice fed
a HF/HFr diet.
Conclusions
Reduced ClpP expression and subsequent mitochondrial dysfunction are key to the development
of diet-induced NASH. ClpP supplementation through viral transduction or chemical
activation represents a potential therapeutic strategy to prevent diet-induced NASH.
Lay summary
Western diets, containing high fat and high fructose, often induce non-alcoholic steatohepatitis
(NASH). Mitochondrial dysfunction is considered pathogenically linked to diet-induced
NASH. We observed that the mitochondrial protease ClpP decreased in the livers of
mice fed a western diet and supplementation of ClpP ameliorated western diet-induced
NASH.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: April 11, 2022
Accepted:
March 21,
2022
Received in revised form:
February 18,
2022
Received:
September 11,
2020
Footnotes
Author names in bold designate shared co-first authorship.
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
