Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism.

Phosphatidate phosphatase-1 (PAP1) enzymes have a key role in glycerolipid synthesis through the conversion of phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine. PAP1 activity in mammals is determined by the lipin family of proteins, lipin-1, lipin-2, and lipin-3, which each have distinct tissue expression patterns and appear to have unique physiological functions. In addition to its role in glycerolipid synthesis, lipin-1 also operates as a transcriptional coactivator, working in collaboration with known nuclear receptors and coactivators to modulate lipid metabolism gene expression. The requirement for different lipin activities in vivo is highlighted by the occurrence of lipodystrophy, insulin resistance, and neuropathy in a lipin-1-deficient mutant mouse strain. In humans, variations in lipin-1 expression levels and gene polymorphisms are associated with insulin sensitivity, metabolic rate, hypertension, and risk for the metabolic syndrome. Furthermore, critical mutations in lipin-2 result in the development of an inflammatory disorder in human patients. A key goal of future studies will be to further elucidate the specific roles and modes of regulation of each of the three lipin proteins in key metabolic processes, including triglyceride and phospholipid synthesis, fatty acid metabolism, and insulin sensitivity.