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.
Highlights
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
Among the AGPAT isoforms, AGPAT2 stands out since null mutations of AGPAT2 are associated with Berardinelli-Seip congenital lipodystrophy type 1 (BSCL1)/congenital generalized lipodystrophy, type 1 (CGL1), which is characterized by a near complete loss of adipose tissue, early onset of insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis[9]
We discover an unexpected link between AGPAT2 and CDS1/2, enzymes that convert PA to CDP-deficiency compromises the stability of CDPdiacylglycerol (DAG) for the synthesis of phospholipids including phosphatidylinositol (PI) and phosphatidylglycerol (PG) (Fig. 1a)
Summary
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. While AGPAT2 catalyzes the acylation of LPA to PA, the level of PA was surprisingly and dramatically increased in AGPAT2-deficient cells and liver[11,12,13]. In this connection, seipin, whose loss-of-function mutations cause BSCL2, regulates the level and distribution of PA14–18. Our results suggest the existence of substrate channelling at a key branch point of the glycerol-3-phosphate pathway for the synthesis of phospholipids and TAGs
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