Glycerolipid / triacylglycerol biosynthesis (glycerol-phosphate pathway) (GPAM -> AGPAT2 -> LPIN1 -> DGAT1/2)

Triacylglycerol (TAG) is the principal energy-storage lipid, assembled from glycerol-3-phosphate and fatty acyl-CoAs by the glycerol-phosphate pathway, whose intermediate diacylglycerol is also the branch point to the major glycerophospholipids. Glycerol-3-phosphate acyltransferase (GPAM/GPAT1, at the mitochondrial outer membrane) performs the first, committed and rate-limiting acylation of sn-glycerol-3-phosphate at sn-1 to lysophosphatidic acid (LPA). 1-Acylglycerol-3-phosphate O-acyltransferase (AGPAT2/LPAAT-beta, at the ER) acylates LPA at sn-2 to phosphatidic acid (PA). The Mg2+-dependent phosphatidate phosphatase lipin-1 (LPIN1) dephosphorylates PA to diacylglycerol (DAG); LPIN1 additionally moonlights in the nucleus as a transcriptional coregulator of lipid-metabolism genes. Finally the diacylglycerol O-acyltransferases DGAT1 (an ER MBOAT-family enzyme with broad acyl-acceptor specificity) and DGAT2 (the ER/lipid-droplet DGAT2- family enzyme that is the quantitatively major TAG synthase) esterify DAG at sn-3 with a fatty acyl-CoA to form TAG - the final, dedicated step, which packages TAG into cytoplasmic lipid droplets. Defects cause metabolic disease: AGPAT2 and (via the pathway) other steps cause congenital generalized lipodystrophy, LPIN1 causes recurrent childhood rhabdomyolysis, and DGAT1 causes a congenital diarrhoea / protein-losing enteropathy.