PMID- 36592658
OWN - NLM
STAT- MEDLINE
DCOM- 20230829
LR  - 20231213
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 64
IP  - 2
DP  - 2023 Feb
TI  - Sterol-regulated transmembrane protein TMEM86a couples LXR signaling to 
      regulation of lysoplasmalogens in macrophages.
PG  - 100325
LID - S0022-2275(22)00158-4 [pii]
LID - 10.1016/j.jlr.2022.100325 [doi]
LID - 100325
AB  - Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central 
      role in plasmalogen metabolism and membrane fluidity. The liver X receptor (LXR) 
      transcription factors are important determinants of cellular lipid homeostasis 
      owing to their ability to regulate cholesterol and fatty acid metabolism. 
      However, their role in governing the composition of lipid species such as 
      lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the 
      lipidome of bone marrow-derived macrophages (BMDMs) following LXR activation. We 
      found a marked reduction in the levels of lysoplasmalogen species in the absence 
      of changes in the levels of plasmalogens themselves. Transcriptional profiling of 
      LXR-activated macrophages identified the gene encoding transmembrane protein 86a 
      (TMEM86a), an integral endoplasmic reticulum protein, as a previously 
      uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct 
      transcriptional target of LXR in macrophages and microglia and that it is highly 
      expressed in TREM2(+)/lipid-associated macrophages in human atherosclerotic 
      plaques, where its expression positively correlates with other LXR-regulated 
      genes. We further show that both murine and human TMEM86a display active 
      lysoplasmalogenase activity that can be abrogated by inactivating mutations in 
      the predicted catalytic site. Consequently, we demonstrate that overexpression of 
      Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, 
      while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels 
      and abrogates the LXR-dependent reduction of this lipid species. Collectively, 
      our findings implicate TMEM86a as a sterol-regulated lysoplasmalogenase in 
      macrophages that contributes to sterol-dependent membrane remodeling.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - van Wouw, Suzanne A E
AU  - van Wouw SAE
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - van den Berg, Marlene
AU  - van den Berg M
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - El Ouraoui, Maroua
AU  - El Ouraoui M
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Meurs, Amber
AU  - Meurs A
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Kingma, Jenina
AU  - Kingma J
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Ottenhoff, Roelof
AU  - Ottenhoff R
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Loix, Melanie
AU  - Loix M
AD  - Department of Immunology and Infection, Biomedical Research Institute, Hasselt 
      University, Diepenbeek, Belgium.
FAU - Hoeksema, Marten A
AU  - Hoeksema MA
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Prange, Koen
AU  - Prange K
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Pasterkamp, Gerard
AU  - Pasterkamp G
AD  - Department of Experimental Cardiology, Utrecht UMC, Utrecht, the Netherlands.
FAU - Hendriks, Jerome J A
AU  - Hendriks JJA
AD  - Department of Immunology and Infection, Biomedical Research Institute, Hasselt 
      University, Diepenbeek, Belgium.
FAU - Bogie, Jeroen F J
AU  - Bogie JFJ
AD  - Department of Immunology and Infection, Biomedical Research Institute, Hasselt 
      University, Diepenbeek, Belgium.
FAU - van Klinken, Jan B
AU  - van Klinken JB
AD  - Amsterdam UMC location University of Amsterdam, Department of Clinical Chemistry 
      and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, 
      Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC location 
      University of Amsterdam, Amsterdam, the Netherlands; Department of Human 
      Genetics, Leiden University Medical Center, Leiden, the Netherlands.
FAU - Vaz, Frederic M
AU  - Vaz FM
AD  - Amsterdam UMC location University of Amsterdam, Department of Clinical Chemistry 
      and Pediatrics, Laboratory Genetic Metabolic Diseases, Emma Children's Hospital, 
      Amsterdam, the Netherlands; Core Facility Metabolomics, Amsterdam UMC location 
      University of Amsterdam, Amsterdam, the Netherlands.
FAU - Jongejan, Aldo
AU  - Jongejan A
AD  - Department of Epidemiology and Data Science, Bioinformatics Laboratory, of 
      Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
FAU - de Winther, Menno P J
AU  - de Winther MPJ
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands.
FAU - Zelcer, Noam
AU  - Zelcer N
AD  - Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Institutes of 
      Cardiovascular Sciences, Infection and Immunity, and Gastroenterology 
      Endocrinology and Metabolism, University of Amsterdam, Amsterdam, the 
      Netherlands. Electronic address: n.zelcer@amsterdamumc.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221231
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (Liver X Receptors)
RN  - 0 (lysoplasmalogens)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Sterols)
RN  - 0 (Transcription Factors)
RN  - 0 (Trem2 protein, mouse)
RN  - 0 (TMEM86a protein, human)
RN  - 0 (Tmem86a protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Liver X Receptors/metabolism
MH  - *Macrophages/metabolism
MH  - Membrane Glycoproteins/metabolism
MH  - Membrane Proteins/metabolism
MH  - Receptors, Immunologic
MH  - *Sterols/metabolism
MH  - Transcription Factors/metabolism
PMC - PMC9926310
OTO - NOTNLM
OT  - LXR
OT  - atherosclerotic plaques
OT  - bone marrow-derived macrophages
OT  - lipid metabolism
OT  - lipidomics
OT  - lysoplasmalogens
OT  - membrane fluidity
OT  - plasmalogens
OT  - sterol
OT  - transcriptional regulation
COIS- Conflict of interest The authors declare no conflict of interest.
EDAT- 2023/01/03 06:00
MHDA- 2023/03/03 06:00
PMCR- 2022/12/31
CRDT- 2023/01/02 19:12
PHST- 2022/10/27 00:00 [received]
PHST- 2022/12/16 00:00 [revised]
PHST- 2022/12/21 00:00 [accepted]
PHST- 2023/01/03 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2023/01/02 19:12 [entrez]
PHST- 2022/12/31 00:00 [pmc-release]
AID - S0022-2275(22)00158-4 [pii]
AID - 100325 [pii]
AID - 10.1016/j.jlr.2022.100325 [doi]
PST - ppublish
SO  - J Lipid Res. 2023 Feb;64(2):100325. doi: 10.1016/j.jlr.2022.100325. Epub 2022 Dec 
      31.