PMID- 35421426
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20230704
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Linking)
VI  - 77
IP  - 3
DP  - 2022 Sep
TI  - Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in 
      mice.
PG  - 735-747
LID - S0168-8278(22)00226-4 [pii]
LID - 10.1016/j.jhep.2022.03.034 [doi]
AB  - 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.
CI  - Copyright (c) 2022 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Choi, Sung-E
AU  - Choi SE
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749.
FAU - Hwang, Yoonjung
AU  - Hwang Y
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749.
FAU - Lee, Soo-Jin
AU  - Lee SJ
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749.
FAU - Jung, Hyunkyung
AU  - Jung H
AD  - Department of Molecular and Integrative Physiology, University of Illinois at 
      Urbana-Champaign, Urbana, Illinois, USA 61801.
FAU - Shin, Tae Hwan
AU  - Shin TH
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749.
FAU - Son, Youngho
AU  - Son Y
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749; Department of Biomedical Science, The Graduate School, 
      Ajou University, Suwon, Gyunggi-do, Republic of Korea 443-749.
FAU - Park, Seokho
AU  - Park S
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749; Department of Biomedical Science, The Graduate School, 
      Ajou University, Suwon, Gyunggi-do, Republic of Korea 443-749.
FAU - Han, Seung Jin
AU  - Han SJ
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Gyunggi-do, Republic of Korea 443-749.
FAU - Kim, Hae Jin
AU  - Kim HJ
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Gyunggi-do, Republic of Korea 443-749.
FAU - Lee, Kwan Woo
AU  - Lee KW
AD  - Department of Endocrinology and Metabolism, Ajou University School of Medicine, 
      Suwon, Gyunggi-do, Republic of Korea 443-749.
FAU - Lee, Gwang
AU  - Lee G
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749.
FAU - Kemper, Jongsook Kim
AU  - Kemper JK
AD  - Department of Molecular and Integrative Physiology, University of Illinois at 
      Urbana-Champaign, Urbana, Illinois, USA 61801.
FAU - Song, Hyun Kyu
AU  - Song HK
AD  - School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of 
      Korea 136-701.
FAU - Kang, Yup
AU  - Kang Y
AD  - Department of Physiology, Ajou University School of Medicine, Suwon, Gyunggi-do, 
      Republic of Korea 443-749. Electronic address: kangy@ajou.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220412
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 2UMI9U37CP (Oleic Acid)
RN  - 30237-26-4 (Fructose)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.21.92 (CLPP protein, mouse)
RN  - EC 3.4.21.92 (Endopeptidase Clp)
SB  - IM
MH  - Animals
MH  - Diet, High-Fat/adverse effects
MH  - Dietary Supplements
MH  - Disease Models, Animal
MH  - Endopeptidase Clp
MH  - Fructose/adverse effects/metabolism
MH  - Liver/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/metabolism
MH  - *Non-alcoholic Fatty Liver Disease/etiology/metabolism/prevention & control
MH  - Oleic Acid/metabolism
MH  - Peptide Hydrolases/metabolism
OTO - NOTNLM
OT  - inflammation
OT  - mitochondrial dysfunction
OT  - proteostasis
OT  - steatohepatitis
COIS- Conflicts of interest The authors declare no conflicts of interest that pertain 
      to this work. Please refer to the accompanying ICMJE disclosure forms for further 
      details.
EDAT- 2022/04/15 06:00
MHDA- 2022/08/23 06:00
CRDT- 2022/04/14 20:10
PHST- 2020/09/11 00:00 [received]
PHST- 2022/02/18 00:00 [revised]
PHST- 2022/03/21 00:00 [accepted]
PHST- 2022/04/15 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/04/14 20:10 [entrez]
AID - S0168-8278(22)00226-4 [pii]
AID - 10.1016/j.jhep.2022.03.034 [doi]
PST - ppublish
SO  - J Hepatol. 2022 Sep;77(3):735-747. doi: 10.1016/j.jhep.2022.03.034. Epub 2022 Apr 
      12.