PMID- 33900381
OWN - NLM
STAT- MEDLINE
DCOM- 20211122
LR  - 20211122
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 478
IP  - 10
DP  - 2021 May 28
TI  - FATP4 inactivation in cultured macrophages attenuates M1- and ER stress-induced 
      cytokine release via a metabolic shift towards triacylglycerides.
PG  - 1861-1877
LID - 10.1042/BCJ20210155 [doi]
AB  - Fatty acid transport protein 4 (FATP4) belongs to a family of acyl-CoA 
      synthetases which activate long-chain fatty acids into acyl-CoAs subsequently 
      used in specific metabolic pathways. Patients with FATP4 mutations and Fatp4-null 
      mice show thick desquamating skin and other complications, however, FATP4 role on 
      macrophage functions has not been studied. We here determined whether the levels 
      of macrophage glycerophospholipids, sphingolipids including ceramides, 
      triacylglycerides, and cytokine release could be altered by FATP4 inactivation. 
      Two in vitro experimental systems were studied: FATP4 knockdown in THP-1-derived 
      macrophages undergoing M1 (LPS + IFNgamma) or M2 (IL-4) activation and bone 
      marrow-derived macrophages (BMDMs) from macrophage-specific Fatp4-knockout 
      (Fatp4M-/-) mice undergoing tunicamycin (TM)-induced endoplasmic reticulum 
      stress. FATP4-deficient macrophages showed a metabolic shift towards 
      triacylglycerides and were protected from M1- or TM-induced release of 
      pro-inflammatory cytokines and cellular injury. Fatp4M-/- BMDMs showed 
      specificity in attenuating TM-induced activation of inositol-requiring enzyme1alpha, 
      but not other unfolded protein response pathways. Under basal conditions, 
      FATP4/Fatp4 deficiency decreased the levels of ceramides and induced an 
      up-regulation of mannose receptor CD206 expression. The deficiency led to an 
      attenuation of IL-8 release in THP-1 cells as well as TNF-alpha and IL-12 release in 
      BMDMs. Thus, FATP4 functions as an acyl-CoA synthetase in macrophages and its 
      inactivation suppresses the release of pro-inflammatory cytokines by shifting 
      fatty acids towards the synthesis of specific lipids.
CI  - (c) 2021 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Zhang, Yuling
AU  - Zhang Y
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Wu, Ning
AU  - Wu N
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Gan-Schreier, Hongying
AU  - Gan-Schreier H
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Xu, Feng
AU  - Xu F
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Tuma-Kellner, Sabine
AU  - Tuma-Kellner S
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Staffer, Simone
AU  - Staffer S
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Seessle, Jessica
AU  - Seessle J
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Merle, Uta
AU  - Merle U
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
FAU - Chamulitrat, Walee
AU  - Chamulitrat W
AUID- ORCID: 0000-0002-5999-7664
AD  - Department of Internal Medicine IV, University of Heidelberg Hospital, Im 
      Neuenheimer Feld 410, 69120 Heidelberg, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Acyl Coenzyme A)
RN  - 0 (Cytokines)
RN  - 0 (Fatty Acid Transport Proteins)
RN  - 0 (Slc27a4 protein, mouse)
RN  - 0 (Triglycerides)
SB  - IM
MH  - Acyl Coenzyme A/metabolism
MH  - Animals
MH  - Cytokines/*metabolism
MH  - *Endoplasmic Reticulum Stress
MH  - Fatty Acid Transport Proteins/*physiology
MH  - Macrophages/*immunology/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Cells/metabolism
MH  - Signal Transduction
MH  - Triglycerides/*metabolism
MH  - *Unfolded Protein Response
OTO - NOTNLM
OT  - ER stress
OT  - ceramides
OT  - fatty acid transport protein 4
OT  - lipidomics
OT  - polarized macrophages
OT  - triacylglycerides
EDAT- 2021/04/27 06:00
MHDA- 2021/11/23 06:00
CRDT- 2021/04/26 12:22
PHST- 2021/03/15 00:00 [received]
PHST- 2021/04/16 00:00 [revised]
PHST- 2021/04/26 00:00 [accepted]
PHST- 2021/04/27 06:00 [pubmed]
PHST- 2021/11/23 06:00 [medline]
PHST- 2021/04/26 12:22 [entrez]
AID - 228461 [pii]
AID - 10.1042/BCJ20210155 [doi]
PST - ppublish
SO  - Biochem J. 2021 May 28;478(10):1861-1877. doi: 10.1042/BCJ20210155.