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AGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway

Author

Listed:
  • Hoi Yin Mak

    (the University of New South Wales)

  • Qian Ouyang

    (Nanjing University)

  • Sergey Tumanov

    (The University of Sydney
    The University of Sydney
    Victor Chang Cardiac Research Institute)

  • Jiesi Xu

    (Chinese Academy of Sciences)

  • Ping Rong

    (Nanjing University)

  • Feitong Dong

    (Southern University of Science and Technology)

  • Sin Man Lam

    (Chinese Academy of Sciences
    Lipidall Technologies Company Limited)

  • Xiaowei Wang

    (Hebei Medical University)

  • Ivan Lukmantara

    (the University of New South Wales)

  • Ximing Du

    (the University of New South Wales)

  • Mingming Gao

    (Hebei Medical University)

  • Andrew J. Brown

    (the University of New South Wales)

  • Xin Gong

    (Southern University of Science and Technology)

  • Guanghou Shui

    (Chinese Academy of Sciences)

  • Roland Stocker

    (The University of Sydney
    Victor Chang Cardiac Research Institute
    The University of Sydney)

  • Xun Huang

    (Chinese Academy of Sciences)

  • Shuai Chen

    (Nanjing University)

  • Hongyuan Yang

    (the University of New South Wales)

Abstract

AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the glycerol-3-phosphate pathway for the synthesis of phospholipids and triacylglycerols. AGPAT2 is the only AGPAT isoform whose loss-of-function mutations cause a severe form of human congenital generalized lipodystrophy. Paradoxically, AGPAT2 deficiency is known to dramatically increase the level of its product, PA. Here, we find that AGPAT2 deficiency impairs the biogenesis and growth of lipid droplets. We show that AGPAT2 deficiency compromises the stability of CDP-diacylglycerol (DAG) synthases (CDSs) and decreases CDS activity in both cell lines and mouse liver. Moreover, AGPAT2 and CDS1/2 can directly interact and form functional complexes, which promote the metabolism of PA along the CDP-DAG pathway of phospholipid synthesis. Our results provide key insights into the regulation of metabolic flux during lipid synthesis and suggest substrate channelling at a major branch point of the glycerol-3-phosphate pathway.

Suggested Citation

  • Hoi Yin Mak & Qian Ouyang & Sergey Tumanov & Jiesi Xu & Ping Rong & Feitong Dong & Sin Man Lam & Xiaowei Wang & Ivan Lukmantara & Ximing Du & Mingming Gao & Andrew J. Brown & Xin Gong & Guanghou Shui , 2021. "AGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27279-4
    DOI: 10.1038/s41467-021-27279-4
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    1. Kashyap Patel & Marc Foretz & Allison Marion & David G. Campbell & Robert Gourlay & Nadia Boudaba & Emilie Tournier & Paul Titchenell & Mark Peggie & Maria Deak & Min Wan & Klaus H. Kaestner & Olga Gö, 2014. "The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver," Nature Communications, Nature, vol. 5(1), pages 1-16, December.
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