PMID- 32102936
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20220531
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 12
IP  - 532
DP  - 2020 Feb 26
TI  - Liver macrophages inhibit the endogenous antioxidant response in 
      obesity-associated insulin resistance.
LID - eaaw9709 [pii]
LID - 10.1126/scitranslmed.aaw9709 [doi]
AB  - Obesity and insulin resistance are risk factors for nonalcoholic fatty liver 
      disease (NAFLD), the most common chronic liver disease worldwide. Because no 
      approved medication nor an accurate and noninvasive diagnosis is currently 
      available for NAFLD, there is a clear need to better understand the link between 
      obesity and NAFLD. Lipid accumulation during obesity is known to be associated 
      with oxidative stress and inflammatory activation of liver macrophages (LMs). 
      However, we show that although LMs do not become proinflammatory during obesity, 
      they display signs of oxidative stress. In livers of both humans and mice, 
      antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) was down-regulated 
      with obesity and insulin resistance, yielding an impaired response to lipid 
      accumulation. At the molecular level, a microRNA-targeting NRF2 protein, miR-144, 
      was elevated in the livers of obese insulin-resistant humans and mice, and 
      specific silencing of miR-144 in murine and human LMs was sufficient to restore 
      NRF2 protein expression and the antioxidant response. These results highlight the 
      pathological role of LMs and their therapeutic potential to restore the impaired 
      endogenous antioxidant response in obesity-associated NAFLD.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works.
FAU - Azzimato, Valerio
AU  - Azzimato V
AUID- ORCID: 0000-0003-4141-961X
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Jager, Jennifer
AU  - Jager J
AUID- ORCID: 0000-0003-3740-9742
AD  - Universite Cote d'Azur, Inserm U1065, C3M, Team Cellular and Molecular 
      Physiopathology of Obesity, 06000 Nice, France.
FAU - Chen, Ping
AU  - Chen P
AUID- ORCID: 0000-0002-8068-1891
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Morgantini, Cecilia
AU  - Morgantini C
AUID- ORCID: 0000-0003-3142-2508
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Levi, Laura
AU  - Levi L
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Barreby, Emelie
AU  - Barreby E
AUID- ORCID: 0000-0002-6467-5280
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Sulen, Andre
AU  - Sulen A
AUID- ORCID: 0000-0002-2053-1760
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Oses, Carolina
AU  - Oses C
AUID- ORCID: 0000-0001-8194-1168
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Willerbrords, Joost
AU  - Willerbrords J
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Xu, Connie
AU  - Xu C
AUID- ORCID: 0000-0002-5032-261X
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Li, Xidan
AU  - Li X
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden.
FAU - Shen, Joanne X
AU  - Shen JX
AD  - Section of Pharmacogenetics, Department of Physiology and Pharmacology, 
      Karolinska Institutet, 171 77 Solna, Sweden.
FAU - Akbar, Naveed
AU  - Akbar N
AUID- ORCID: 0000-0003-4620-6373
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, OX3 9DU Oxford, UK.
FAU - Haag, Lars
AU  - Haag L
AD  - Department of Laboratory Medicine, Laboratory Medicine, Karolinska Institutet, 
      141 57 Huddinge, Sweden.
FAU - Ellis, Ewa
AU  - Ellis E
AUID- ORCID: 0000-0002-3057-5337
AD  - Division of Transplantation Surgery, Clinical Science, Intervention and 
      Technology (CLINTEC), Karolinska Institutet, 141 57 Huddinge, Sweden.
FAU - Walhen, Kerstin
AU  - Walhen K
AD  - Unit of Endocrinology Department of Medicine, Karolinska Institutet, 141 57 
      Huddinge, Sweden.
FAU - Naslund, Erik
AU  - Naslund E
AUID- ORCID: 0000-0002-0166-6344
AD  - Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, 
      Karolinska Institutet, 182 88 Stockholm, Sweden.
FAU - Thorell, Anders
AU  - Thorell A
AUID- ORCID: 0000-0001-7238-1728
AD  - Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, 
      Karolinska Institutet, 182 88 Stockholm, Sweden.
AD  - Department of Surgery, Ersta Hospital, Karolinska Institutet, 116 28 Stockholm, 
      Sweden.
FAU - Choudhury, Robin P
AU  - Choudhury RP
AUID- ORCID: 0000-0002-8046-1688
AD  - Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University 
      of Oxford, OX3 9DU Oxford, UK.
FAU - Lauschke, Volker M
AU  - Lauschke VM
AUID- ORCID: 0000-0002-1140-6204
AD  - Section of Pharmacogenetics, Department of Physiology and Pharmacology, 
      Karolinska Institutet, 171 77 Solna, Sweden.
FAU - Ryden, Mikael
AU  - Ryden M
AUID- ORCID: 0000-0003-4785-1876
AD  - Unit of Endocrinology Department of Medicine, Karolinska Institutet, 141 57 
      Huddinge, Sweden.
FAU - Craige, Siobhan M
AU  - Craige SM
AD  - Human Nutrition, Food, and Exercise Department, Virginia Tech, Blacksburg, VA 
      24060, USA.
FAU - Aouadi, Myriam
AU  - Aouadi M
AUID- ORCID: 0000-0001-6256-7107
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, 141 57 Huddinge, Sweden. myriam.aouadi@ki.se.
LA  - eng
GR  - PG/18/53/33895/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antioxidants)
RN  - 0 (MIRN144 microRNA, human)
RN  - 0 (MIRN144 microRNA, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nfe2l2 protein, mouse)
SB  - IM
MH  - Animals
MH  - *Antioxidants
MH  - Humans
MH  - *Insulin Resistance
MH  - *Kupffer Cells
MH  - Liver
MH  - Mice
MH  - MicroRNAs
MH  - NF-E2-Related Factor 2
MH  - *Non-alcoholic Fatty Liver Disease
MH  - Obesity
EDAT- 2020/02/28 06:00
MHDA- 2021/06/24 06:00
CRDT- 2020/02/28 06:00
PHST- 2019/02/11 00:00 [received]
PHST- 2020/02/06 00:00 [accepted]
PHST- 2020/02/28 06:00 [entrez]
PHST- 2020/02/28 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
AID - 12/532/eaaw9709 [pii]
AID - 10.1126/scitranslmed.aaw9709 [doi]
PST - ppublish
SO  - Sci Transl Med. 2020 Feb 26;12(532):eaaw9709. doi: 10.1126/scitranslmed.aaw9709.