Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice

Sung E. Choi, Yoonjung Hwang, Soo Jin Lee, Hyunkyung Jung, Tae Hwan Shin, Youngho Son, Seokho Park, Seung Jin Han, Hae Jin Kim, Kwan Woo Lee, Gwang Lee, Jongsook Kim Kemper, Hyun Kyu Song, Yup Kang

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)735-747
Number of pages13
JournalJournal of Hepatology
Volume77
Issue number3
DOIs
Publication statusPublished - 2022 Sep

Keywords

  • inflammation
  • mitochondrial dysfunction
  • proteostasis
  • steatohepatitis

ASJC Scopus subject areas

  • Hepatology

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