Mammalian lipin phosphatidic acid phosphatases in lipid synthesis and beyond: metabolic and inflammatory disorders

Abstract

The regulation of cellular lipid storage and membrane lipid composition plays a critical role in metabolic homeostasis, and dysregulation may contribute to disorders such as obesity, fatty liver, type 2 diabetes, and cardiovascular disease. The mammalian lipin proteins (lipin 1, lipin 2, and lipin 3) are phosphatidic acid phosphatase (PAP) enzymes that modulate levels of cellular triacylglycerols and phospholipids, and also regulate lipid intermediates in cellular signaling pathways. Lipin proteins also have the ability to coactivate/corepress transcription. In humans and mice, lipin gene mutations cause severe metabolic phenotypes including rhabdomyolysis (lipin 1), autoinflammatory disease (lipin 2), and impaired intestinal lipoprotein assembly (lipin 2/lipin 3). Characterization of these diseases has revealed roles for lipin PAP activity in fundamental cellular processes such as autophagy, inflammasome activation, and lipoprotein assembly. Lipin protein activity is regulated at pre- and posttranscriptional levels, which suggests a need for their ordered response to specific physiological stimuli. Challenges for the future include better elucidation of the unique biochemical and physiological properties of individual lipin family members and determination of lipin protein structure-function relationships. Further research may propel exploration of lipin proteins as viable therapeutic targets in metabolic or inflammatory disorders.

Keywords: autophagy; chylomicron; inflammasome; lipodystrophy; lipoprotein; obesity; phospholipid; rhabdomyolysis; triacylglycerol.

Graphical abstract

Fig. 1.

Pathways for glycerolipid synthesis. The glycerol 3-phosphate (G3P) pathway modifies a glycerol 3-phosphate backbone by the action of acyltransferases and lipin PAP to form TAG and phospholipids. With the MAG pathway, MGAT acts on dietary-derived MAG and fatty acids to synthesize TAG. GPAT, glycerol 3-phosphate acyltransferase; AGPAT, 1-acylglycerol-3-phosphate acyltransferase; DGAT, acyl-CoA:diacylglycerol acyltransferase; LPA, lysophosphatidic acid; zwitterionic phospholipids (PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine); anionic phospholipids (CL, cardiolipin; PI, phosphatidylinositol; PG, phosphoglycerate).

Fig. 2.

Posttranslational lipin protein modifications regulate subcellular localization and activity. Modifications that promote lipin 1 translocation to the ER membrane (and membranes of other organelles such as autophagosomes/lysosomes) regulate PAP activity by allowing lipin protein access to its substrate, PA. Insulin, mammalian target of rapamycin (mTOR), and casein kinase activities all lead to lipin 1 phosphorylation (40, 43, 48). Hyperphosphorylated lipin 1 associates with 14-3-3 proteins and is retained in the cytoplasm (45). The CTD-NEP/NEP1-R1 phosphatase complex dephosphorylates lipin 1 and promotes membrane association (46). Lipin 1 membrane association is also promoted by acetylation via the TIP60 acetyltransferase (47), and lipin 1 sumoylation enhances nuclear localization (44). Polyubiquitination primes lipin 1 for degradation (48). P, phospho group; Ac, acetyl group, Ub, ubiquitin; CK, casein kinase; mTORC1, mammalian target of rapamycin complex 1; SIRT1, sirtuin 1; SCF^b-TRCP, SCF(Skp1/Cullin1/F-box protein) E3 ubiquitin ligase complex/F-box protein b-transducin repeat-containing protein; SUMO, sumoylation sites; TFs, transcription factors.