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PreprintCited by 9Lipid metabolism and biosynthesisSphingolipid Metabolism and SignalingPeroxisome Proliferator-Activated Receptors

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Cyclic phosphatidic acid is produced by GDE7 in the ER lumen as a lysophospholipid mediator

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Kitakaze, Keisuke, Ali, Hanif, Kimoto, Raiki, Takenouchi, Yasuhiro, Ishimaru, Hironobu, Yamashita, Atsushi, Ueda, Natsuo, Tanaka, Tamotsu, Okamoto, Yasuo, Tsuboi, Kazuhito·2022·Communications Biology
DOI 10.21203/rs.3.rs-2152597/v1PMC PMC10188492

Preprint — published as 10.1038/s42003-023-04900-4 · Paper page

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Abstract

Cyclic phosphatidic acid (cPA) is a lipid mediator, which regulates adipogenesis and glucose homeostasis by suppressing nuclear peroxisome proliferator-activated receptor γ (PPARγ). Glycerophosphodiesterase 7 (GDE7) is a Ca 2+-dependent lysophospholipase D that localizes in the endoplasmic reticulum. Although mouse GDE7 catalyzes cPA production in a cell-free system, it is unknown whether GDE7 generates cPA in living cells. Here, we demonstrate that human GDE7 possesses cPA-producing activity in living cells as well as in a cell-free system. Furthermore, the active site of human GDE7 is directed towards the luminal side of the endoplasmic reticulum. Mutagenesis revealed that amino acid residues F227 and Y238 are important for catalytic activity. GDE7 deficiency derepresses the PPARγ pathway in human mammary MCF-7 cells, suggesting that cPA functions as an intracellular lipid mediator. These findings lead to a better understanding of the biological role of GDE7 and its product, cPA.

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Metadata

Authors
Kitakaze, K., Ali, H., Kimoto, R., Takenouchi, Y., Ishimaru, H., Yamashita, A., Ueda, N., Tanaka, T., Okamoto, Y., & Tsuboi, K.
Affiliations
  • Kawasaki Medical School (JP)
  • Tokushima University (JP)
  • Teikyo University (JP)
  • Kagawa University (JP)
Corresponding author
  • Kitakaze, Keisuke
  • Tsuboi, Kazuhito
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2022-10-27
Volume
6
Issue
1
Pages
524-524
ISSN
2399-3642 (ISSN-L)
DOI
10.21203/rs.3.rs-2152597/v1
PMC
PMC10188492
OpenAlex
W4376872782
Cited by
9
References
1
Citations by year
2025: 2 · 2024: 5 · 2023: 2
FWCI
0.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders
  • CSL Behring
  • Asahi Kasei Pharma Corporation (APJS20220406011)
  • EA Pharma Co., Ltd.
  • Ministry of Education, Culture, Sports, Science and Technology (JP20K19732, JP20K11571)
  • Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care (2020-23)
  • Kyowa Hakko Kirin (KKCS20210402007 and KKCS20220401021)
  • Senko Medical Instrument Manufacturing Company
  • Otsuka Pharmaceutical (AS2022A000441768)
  • Kawasaki Medical School (R01S-002, R02S-002, and R04Y-001, R02S-002, and R04Y-001, R01S-002)
  • Teijin Pharma (TJNS20200413014, TJNS20210412018, and TJNS20220411014, TJNS20210412018, and TJNS20220411014, TJNS20200413014)
  • Japan Society for the Promotion of Science (20K19732, 23K14810, 20K11571, 22K06114, 23K10973, 22K06584, 22K06885, 22K08295)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
cyclic phosphatidic acid, autotaxin, endoplasmic reticulum lumen, PPARγ, adipogenesis, glucose homeostasis, active site residues, MCF-7 cells, 3T3-L1 preadipocytes
MeSH terms
Animals, Endoplasmic Reticulum, Humans, Lysophospholipids, Phosphatidic Acids, Phosphoric Diester Hydrolases, PPAR gamma, Mice

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