Nature Communications
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.
| 论文编号: | DOI:10.1038/s41467-021-27279-4 |
| 论文题目: | AGPAT2 Interaction with CDP-Diacylglycerol Synthases Promotes the Flux of Fatty Acids Through the CDP-Diacylglycerol Pathway |
| 英文论文题目: | AGPAT2 Interaction with CDP-Diacylglycerol Synthases Promotes the Flux of Fatty Acids Through the CDP-Diacylglycerol Pathway |
| 第一作者: | 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 & Hongyuan Yang |
| 英文第一作者: | 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 & Hongyuan Yang |
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| 发表年度: | 2021-12-06 |
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| 摘要: | 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. |
| 英文摘要: | 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. |
| 刊物名称: | Nature Communications |
| 英文刊物名称: | Nature Communications |
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| 其它备注: | 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 & Hongyuan Yang. AGPAT2 Interaction with CDP-Diacylglycerol Synthases Promotes the Flux of Fatty Acids Through the CDP-Diacylglycerol Pathway. Nature Communications. DOI:10.1038/s41467-021-27279-4 |
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