PMID- 36752206
OWN - NLM
STAT- MEDLINE
DCOM- 20230210
LR  - 20240515
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 8
IP  - 3
DP  - 2023 Feb 8
TI  - Notch-mediated hepatocyte MCP-1 secretion causes liver fibrosis.
LID - 10.1172/jci.insight.165369 [doi]
LID - e165369
AB  - Patients with nonalcoholic steatohepatitis (NASH) have increased expression of 
      liver monocyte chemoattractant protein-1 (MCP-1), but its cellular source and 
      contribution to various aspects of NASH pathophysiology remain debated. We 
      demonstrated increased liver CCL2 (which encodes MCP-1) expression in patients 
      with NASH, and commensurately, a 100-fold increase in hepatocyte Ccl2 expression 
      in a mouse model of NASH, accompanied by increased liver monocyte-derived 
      macrophage (MoMF) infiltrate and liver fibrosis. To test repercussions of 
      increased hepatocyte-derived MCP-1, we generated hepatocyte-specific 
      Ccl2-knockout mice, which showed reduced liver MoMF infiltrate as well as 
      decreased liver fibrosis. Forced hepatocyte MCP-1 expression provoked the 
      opposite phenotype in chow-fed wild-type mice. Consistent with increased 
      hepatocyte Notch signaling in NASH, we observed a close correlation between 
      markers of Notch activation and CCL2 expression in patients with NASH. We found 
      that an evolutionarily conserved Notch/recombination signal binding protein for 
      immunoglobulin kappa J region binding site in the Ccl2 promoter mediated 
      transactivation of the Ccl2 promoter in NASH diet-fed mice. Increased liver MoMF 
      infiltrate and liver fibrosis seen in opposite gain-of-function mice was 
      ameliorated with concomitant hepatocyte Ccl2 knockout or CCR2 inhibitor 
      treatment. Hepatocyte Notch activation prompts MCP-1-dependent increase in liver 
      MoMF infiltration and fibrosis.
FAU - Kang, Jinku
AU  - Kang J
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
FAU - Postigo-Fernandez, Jorge
AU  - Postigo-Fernandez J
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
AD  - Columbia Center for Translational Immunology, Columbia University Irving Medical 
      Center, New York, New York, USA.
FAU - Kim, KyeongJin
AU  - Kim K
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
AD  - Department of Biomedical Sciences, College of Medicine, Program in Biomedical 
      Science & Engineering, and Research Center for Controlling Intercellular 
      Communication (RCIC), Inha University, Incheon, South Korea.
FAU - Zhu, Changyu
AU  - Zhu C
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
AD  - Memorial Sloan Kettering Cancer Center, New York, New York, USA.
FAU - Yu, Junjie
AU  - Yu J
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
FAU - Meroni, Marica
AU  - Meroni M
AD  - General Medicine and Metabolic Diseases, Fondazione IRCCS Ca Granda Ospedale 
      Maggiore Policlinico, Milan, Italy.
FAU - Mayfield, Brent
AU  - Mayfield B
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
FAU - Bartolome, Alberto
AU  - Bartolome A
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
AD  - Instituto de Investigaciones Biomedicas Alberto Sols (CSIC/UAM), Madrid, Spain.
FAU - Dapito, Dianne H
AU  - Dapito DH
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
FAU - Ferrante, Anthony W Jr
AU  - Ferrante AW Jr
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
FAU - Dongiovanni, Paola
AU  - Dongiovanni P
AD  - General Medicine and Metabolic Diseases, Fondazione IRCCS Ca Granda Ospedale 
      Maggiore Policlinico, Milan, Italy.
FAU - Valenti, Luca
AU  - Valenti L
AD  - Department of Pathophysiology and Transplantation, Universita degli Studi di 
      Milano, Milan, Italy.
AD  - Precision Medicine Lab, Biological Resource Center, Department of Transfusion 
      Medicine and Hematology, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico 
      Milan, Milan, Italy.
FAU - Creusot, Remi J
AU  - Creusot RJ
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
AD  - Columbia Center for Translational Immunology, Columbia University Irving Medical 
      Center, New York, New York, USA.
FAU - Pajvani, Utpal B
AU  - Pajvani UB
AD  - Department of Medicine, Naomi Berrie Diabetes Center, and.
LA  - eng
GR  - R01 DK103818/DK/NIDDK NIH HHS/United States
GR  - R01 DK119767/DK/NIDDK NIH HHS/United States
GR  - P30 DK063608/DK/NIDDK NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - R01 DK066525/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230208
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Chemokine CCL2)
RN  - 0 (Ccl2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Chemokine CCL2/metabolism
MH  - Hepatocytes/metabolism
MH  - Liver Cirrhosis/pathology
MH  - *Non-alcoholic Fatty Liver Disease/metabolism
PMC - PMC9977430
OTO - NOTNLM
OT  - Chemokines
OT  - Fibrosis
OT  - Gastroenterology
OT  - Metabolism
COIS- Conflict of interest: The authors have declared that no conflict of interest 
      exists.
EDAT- 2023/02/09 06:00
MHDA- 2023/02/10 06:00
PMCR- 2023/02/08
CRDT- 2023/02/08 06:03
PHST- 2022/09/13 00:00 [received]
PHST- 2022/12/29 00:00 [accepted]
PHST- 2023/02/08 06:03 [entrez]
PHST- 2023/02/09 06:00 [pubmed]
PHST- 2023/02/10 06:00 [medline]
PHST- 2023/02/08 00:00 [pmc-release]
AID - 165369 [pii]
AID - 10.1172/jci.insight.165369 [doi]
PST - epublish
SO  - JCI Insight. 2023 Feb 8;8(3):e165369. doi: 10.1172/jci.insight.165369.