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

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, Roland Stocker, Xun Huang, Shuai Chen and Hongyuan Yang ()
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Hoi Yin Mak: the University of New South Wales
Qian Ouyang: Nanjing University
Sergey Tumanov: The University of Sydney
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
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
Xun Huang: Chinese Academy of Sciences
Shuai Chen: Nanjing University
Hongyuan Yang: the University of New South Wales

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27279-4

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