PMID- 34425095
OWN - NLM
STAT- MEDLINE
DCOM- 20220118
LR  - 20220815
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 161
IP  - 6
DP  - 2021 Dec
TI  - Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During 
      Obesity.
PG  - 1982-1997.e11
LID - S0016-5085(21)03410-7 [pii]
LID - 10.1053/j.gastro.2021.08.030 [doi]
AB  - BACKGROUND AND AIMS: Oxidative stress plays a key role in the development of 
      metabolic complications associated with obesity, including insulin resistance and 
      the most common chronic liver disease worldwide, nonalcoholic fatty liver 
      disease. We have recently discovered that the microRNA miR-144 regulates protein 
      levels of the master mediator of the antioxidant response, nuclear factor 
      erythroid 2-related factor 2 (NRF2). On miR-144 silencing, the expression of NRF2 
      target genes was significantly upregulated, suggesting that miR-144 controls NRF2 
      at the level of both protein expression and activity. Here we explored a 
      mechanism whereby hepatic miR-144 inhibited NRF2 activity upon obesity via the 
      regulation of the tricarboxylic acid (TCA) metabolite, fumarate, a potent 
      activator of NRF2. METHODS: We performed transcriptomic analysis in liver 
      macrophages (LMs) of obese mice and identified the immuno-responsive gene 1 
      (Irg1) as a target of miR-144. IRG1 catalyzes the production of a TCA derivative, 
      itaconate, an inhibitor of succinate dehydrogenase (SDH). TCA enzyme activities 
      and kinetics were analyzed after miR-144 silencing in obese mice and human liver 
      organoids using single-cell activity assays in situ and molecular dynamic 
      simulations. RESULTS: Increased levels of miR-144 in obesity were associated with 
      reduced expression of Irg1, which was restored on miR-144 silencing in vitro and 
      in vivo. Furthermore, miR-144 overexpression reduces Irg1 expression and the 
      production of itaconate in vitro. In alignment with the reduction in IRG1 levels 
      and itaconate production, we observed an upregulation of SDH activity during 
      obesity. Surprisingly, however, fumarate hydratase (FH) activity was also 
      upregulated in obese livers, leading to the depletion of its substrate fumarate. 
      miR-144 silencing selectively reduced the activities of both SDH and FH resulting 
      in the accumulation of their related substrates succinate and fumarate. Moreover, 
      molecular dynamics analyses revealed the potential role of itaconate as a 
      competitive inhibitor of not only SDH but also FH. Combined, these results 
      demonstrate that silencing of miR-144 inhibits the activity of NRF2 through 
      decreased fumarate production in obesity. CONCLUSIONS: Herein we unravel a novel 
      mechanism whereby miR-144 inhibits NRF2 activity through the consumption of 
      fumarate by activation of FH. Our study demonstrates that hepatic miR-144 
      triggers a hyperactive FH in the TCA cycle leading to an impaired antioxidant 
      response in obesity.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Azzimato, Valerio
AU  - Azzimato V
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden. Electronic address: valerio.azzimato@ki.se.
FAU - Chen, Ping
AU  - Chen P
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Barreby, Emelie
AU  - Barreby E
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Morgantini, Cecilia
AU  - Morgantini C
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Levi, Laura
AU  - Levi L
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Vankova, Ana
AU  - Vankova A
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Jager, Jennifer
AU  - Jager J
AD  - Universite Cote d'Azur, Inserm, Centre Mediterraneen de Medecine Moleculaire 
      (C3M), Team << Cellular and Molecular Pathophysiology of Obesity and Diabetes,>> 
      Cote d'Azur, France.
FAU - Sulen, Andre
AU  - Sulen A
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Diotallevi, Marina
AU  - Diotallevi M
AD  - BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe 
      Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, 
      UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
FAU - Shen, Joanne X
AU  - Shen JX
AD  - Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden.
FAU - Miller, Anne
AU  - Miller A
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
FAU - Ellis, Ewa
AU  - Ellis E
AD  - Division of Transplantation Surgery, Department of Clinical Science, Intervention 
      and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.
FAU - Ryden, Mikael
AU  - Ryden M
AD  - Department of Medicine (H7), Karolinska Institutet, Huddinge, Sweden.
FAU - Naslund, Erik
AU  - Naslund E
AD  - Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 
      Stockholm, Sweden.
FAU - Thorell, Anders
AU  - Thorell A
AD  - Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 
      Stockholm, Sweden; Department of Surgery, Ersta Hospital, Karolinska Institutet, 
      Stockholm, Sweden.
FAU - Lauschke, Volker M
AU  - Lauschke VM
AD  - Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden; 
      Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, 
      Germany.
FAU - Channon, Keith M
AU  - Channon KM
AD  - BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe 
      Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, 
      UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
FAU - Crabtree, Mark J
AU  - Crabtree MJ
AD  - BHF Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe 
      Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, 
      UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
FAU - Haschemi, Arvand
AU  - Haschemi A
AD  - Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
FAU - Craige, Siobhan M
AU  - Craige SM
AD  - Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, 
      Virginia.
FAU - Mori, Mattia
AU  - Mori M
AD  - Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, 
      Italy.
FAU - Spallotta, Francesco
AU  - Spallotta F
AD  - Institute for Systems Analysis and Computer Science "A. Ruberti," National 
      Research Council (IASI - CNR), Rome, Italy.
FAU - Aouadi, Myriam
AU  - Aouadi M
AD  - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden. Electronic address: myriam.aouadi@ki.se.
LA  - eng
GR  - CH/16/1/32013/BHF_/British Heart Foundation/United Kingdom
GR  - FS/14/56/31049/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210821
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Fumarates)
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)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Succinates)
RN  - EC 4.1.1.- (ACOD1 protein, human)
RN  - EC 4.1.1.- (Carboxy-Lyases)
RN  - EC 4.2.1.- (Hydro-Lyases)
RN  - EC 4.2.1.2 (Fumarate Hydratase)
RN  - EC 4.2.1.79 (Irg1 protein, mouse)
RN  - Q4516562YH (itaconic acid)
SB  - IM
CIN - Gastroenterology. 2022 May;162(6):1783-1784. PMID: 34998801
CIN - Gastroenterology. 2022 May;162(6):1784-1785. PMID: 35077756
EIN - Gastroenterology. 2022 Oct;163(4):1133. PMID: 35970618
MH  - Animals
MH  - Carboxy-Lyases/genetics/metabolism
MH  - Citric Acid Cycle
MH  - Disease Models, Animal
MH  - Fatty Liver/*enzymology/genetics
MH  - Fumarate Hydratase/genetics/*metabolism
MH  - Fumarates/metabolism
MH  - Humans
MH  - Hydro-Lyases/genetics/metabolism
MH  - *Insulin Resistance
MH  - Liver/*enzymology
MH  - Macrophages/*enzymology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/genetics/*metabolism
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Obesity/*enzymology/genetics
MH  - Oxidative Stress
MH  - RAW 264.7 Cells
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction
MH  - Succinates/metabolism
OTO - NOTNLM
OT  - Fumarase
OT  - Liver
OT  - Metabolism
OT  - Oxidative Stress
OT  - miRNAs
EDAT- 2021/08/24 06:00
MHDA- 2022/01/19 06:00
CRDT- 2021/08/23 20:11
PHST- 2020/08/18 00:00 [received]
PHST- 2021/08/04 00:00 [revised]
PHST- 2021/08/15 00:00 [accepted]
PHST- 2021/08/24 06:00 [pubmed]
PHST- 2022/01/19 06:00 [medline]
PHST- 2021/08/23 20:11 [entrez]
AID - S0016-5085(21)03410-7 [pii]
AID - 10.1053/j.gastro.2021.08.030 [doi]
PST - ppublish
SO  - Gastroenterology. 2021 Dec;161(6):1982-1997.e11. doi: 
      10.1053/j.gastro.2021.08.030. Epub 2021 Aug 21.