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

Abstract

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.

Fig. 1.

Dual molecular functions of lipin proteins as enzymes in glycerolipid biosynthesis and transcriptional coactivation. Left: Lipin proteins act as phosphatidate phosphatase-1 (PAP1) enzymes that catalyze the conversion of phosphatidate (PA) to diacylglycerol (DAG), a direct precursor of triacylglycerol (TAG) and of the phospholipids, phosphatidylethanolamine (PE), and phosphatidylcholine (PC). The acyltransferase enzymes that are required for TAG synthesis (GPAT, glycerol-3-phosphate acyltransferase; AGPAT, acylglycerol-3-phosphate acyltransferase; DGAT, diacylglycerol acyltransferase) are constitutive residents of the endoplasmic reticulum (ER) membrane. In contrast, lipin proteins reside in the cytosol and associate transiently with the ER membrane to perform the PAP1 reaction. Right: Lipin-1 also acts as a transcriptional coactivator that amplifies the effect of known coactivators on transcription of fatty acid oxidation genes. This occurs through lipin-1 interaction with peroxisome proliferator activated receptor γ coactivator-1α (PGC1α) and the nuclear receptor PPARα in a coactivation complex that likely includes other factors such as histone acetyltransferase (HAT). The coactivator activity has thus far been reported primarily for lipin-1, but lipin-2 and -3 proteins possess similar sequence motifs and could exhibit similar activity, although the physiological context for coactivator function of lipin-2 and -3 remains to be determined.

Fig. 2.

Lipin protein structure and functional motifs. A: Schematic view of lipin protein structure with known functional domains indicated. N-LIP and C-LIP regions represent domains that are highly conserved evolutionarily. The C-LIP domain contains critical functional motifs for PAP1 enzyme activity and coactivator interaction. A lysine and arginine-rich nuclear localization signal (NLS) is found in lipin proteins from most species. The alternatively spliced exon present in lipin-1B but not -1A is also indicated. B: Relative PAP1 and coactivator activities of lipin-1 proteins carrying mutation in the PAP1 motif (mDXDXT) or the coactivator interaction motif (mLXXIL). Lipin-1 protein carrying a mutation in the PAP1 active site motif (mDXDXT) lacks PAP1 activity, but retains coactivator function. In contrast, mutation of the coactiviator motif (mLXXIL) abolishes PAP1 and coactivator function. wt, wild-type lipin-1 protein. ** P < 0.001 vs. wt. (Data shown from the authors' laboratories; based on observations presented in Ref. .)

Fig. 3.

Proposed physiological regulation and role of lipin-1 in adipose tissue development and metabolism. Increased glucocorticoid action stimulates Lpin1 transcription and increases lipin-1 protein levels (1). Insulin and other adipogenic factors stimulate lipin-1 activity in an unknown manner, promoting expression of PPARγ and other transcription factors, which induce adipogenic and lipogenic gene expression. Increased lipin-1 PAP1 activity also stimulates TAG synthesis and accumulation to form mature adipocytes (2). During starvation, effects of adrenaline and fatty acids cause lipin-1 translocation to the ER to facilitate incorporation into TAG of fatty acids released during lipolysis (3). The model is based on literature described in the text.

Fig. 4.

Proposed physiological regulation and role of lipin-1 in hepatic lipid metabolism and insulin resistance. Under conditions of insulin resistance, increased action of glucocorticoids relative to insulin stimulates Lpin1 transcription and increases lipin-1 protein levels and PAP1 activity (1). Lack of suppression of adipose tissue lipolysis by insulin increases the fatty acid supply to the liver, which provides substrate for TAG synthesis and β-oxidation. Fatty acids also activate lipin-1 PAP1 activity by promoting its translocation to the ER membrane (2). Translocation of lipin-1 to the ER stimulates TAG synthesis and accumulation, which could potentially lead to steatosis (3). Increased TAG synthesis also influences the rate of VLDL secretion (4). Lipin-1 coactivator activity in conjunction with PGC-1α and PPARα increases transcription of genes involved in fatty acid oxidation and modulates rate of VLDL synthesis and secretion. It may also influence gluconeogenesis (5). The model is based on literature described in the text.