PMID- 32360132
OWN - NLM
STAT- MEDLINE
DCOM- 20210719
LR  - 20210719
IS  - 1878-3562 (Electronic)
IS  - 1590-8658 (Linking)
VI  - 52
IP  - 6
DP  - 2020 Jun
TI  - Mitochondrial DNA from hepatocytes induces upregulation of interleukin-33 
      expression of macrophages in nonalcoholic steatohepatitis.
PG  - 637-643
LID - S1590-8658(20)30123-7 [pii]
LID - 10.1016/j.dld.2020.03.021 [doi]
AB  - OBJECTIVE: In the present study, we propose that lipotoxicity induces the release 
      of mitochondrial DNA (mtDNA) from hepatocytes, which in turn upregulates IL-33 
      expression in macrophages. METHODS: The mtDNA levels of plasma were determined in 
      methionine- and mholine-deficient diet (MCD)-fed mice and NASH patients. Cultured 
      hepatocytes were pre-incubated with Mito-TEMPO or rapamycin and were then 
      stimulated with palmitic acid. The mtDNA levels in the cytosol were measured. The 
      mtDNA from hepatocytes of mice was added to bone marrow-derived macrophages 
      (BMDMs) in the presence of IRS (TLR9 antagonist). The expression of IL-33 in 
      BMDMs was measured. RESULTS: Levels of mtDNA were higher in NASH patients and 
      MCD-fed mice. Treatment of hepatocytes with palmitic acid in vitro induced mtDNA 
      release into cytosol, which was attenuated by mito-TEMPO or rapamycin, and 
      aggravated by inhibition of autophagy. Treatment of BMDMs with mtDNA enhanced 
      IL-33 expression, which was attenuated by knockdown of TLR9. Treatment of BMDMs 
      with mtDNA enhanced lipopolysaccharide (LPS)-induced production of IL-1beta and 
      TNF-alpha, which was attenuated by pretreatment with soluble ST2. CONCLUSION: mtDNA 
      released from injured hepatocytes under lipid overload induced the upregulation 
      of IL-33 expression in macrophages via TLR9, and enhanced LPS-induced 
      inflammatory cytokine production.
CI  - Copyright (c) 2020 Editrice Gastroenterologica Italiana S.r.l. Published by 
      Elsevier Ltd. All rights reserved.
FAU - Gao, Yinjie
AU  - Gao Y
AD  - Department of Pathology and Hepatology, the 5th Medical Centre, Chinese PLA 
      General Hospital, No. 100, Xisi Ring Middle Road, Beijing, 100039, China; Liver 
      Transplantation and Research Center, the 5th Medical Centre, Chinese PLA General 
      Hospital, No. 100, Xisi Ring Middle Road, Beijing, 100039, China.
FAU - Wang, Yijin
AU  - Wang Y
AD  - Department of Pathology and Hepatology, the 5th Medical Centre, Chinese PLA 
      General Hospital, No. 100, Xisi Ring Middle Road, Beijing, 100039, China.
FAU - Liu, Hongling
AU  - Liu H
AD  - Liver Transplantation and Research Center, the 5th Medical Centre, Chinese PLA 
      General Hospital, No. 100, Xisi Ring Middle Road, Beijing, 100039, China.
FAU - Liu, Zhenwen
AU  - Liu Z
AD  - Liver Transplantation and Research Center, the 5th Medical Centre, Chinese PLA 
      General Hospital, No. 100, Xisi Ring Middle Road, Beijing, 100039, China. 
      Electronic address: 13911395948@139.com.
FAU - Zhao, Jingmin
AU  - Zhao J
AD  - Department of Pathology and Hepatology, the 5th Medical Centre, Chinese PLA 
      General Hospital, No. 100, Xisi Ring Middle Road, Beijing, 100039, China. 
      Electronic address: jmzhao302@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200429
PL  - Netherlands
TA  - Dig Liver Dis
JT  - Digestive and liver disease : official journal of the Italian Society of 
      Gastroenterology and the Italian Association for the Study of the Liver
JID - 100958385
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Il33 protein, mouse)
RN  - 0 (Interleukin-33)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tlr9 protein, mouse)
RN  - 0 (Toll-Like Receptor 9)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - DNA, Mitochondrial/*physiology
MH  - Diet, High-Fat/adverse effects
MH  - Hepatocytes/metabolism
MH  - Humans
MH  - Interleukin-33/*metabolism
MH  - Lipopolysaccharides
MH  - Macrophages/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Non-alcoholic Fatty Liver Disease/*metabolism/pathology
MH  - Toll-Like Receptor 9/antagonists & inhibitors/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Up-Regulation
OTO - NOTNLM
OT  - Interleukin-33
OT  - Lipopolysaccharide
OT  - Mitochondrial DNA
OT  - Nonalcoholic steatohepatitis
OT  - Toll-like receptor 9
EDAT- 2020/05/04 06:00
MHDA- 2021/07/20 06:00
CRDT- 2020/05/04 06:00
PHST- 2019/02/09 00:00 [received]
PHST- 2020/03/23 00:00 [revised]
PHST- 2020/03/25 00:00 [accepted]
PHST- 2020/05/04 06:00 [pubmed]
PHST- 2021/07/20 06:00 [medline]
PHST- 2020/05/04 06:00 [entrez]
AID - S1590-8658(20)30123-7 [pii]
AID - 10.1016/j.dld.2020.03.021 [doi]
PST - ppublish
SO  - Dig Liver Dis. 2020 Jun;52(6):637-643. doi: 10.1016/j.dld.2020.03.021. Epub 2020 
      Apr 29.