Three Mammalian Lipins Act as Phosphatidate Phosphatases with Distinct Tissue Expression Patterns

Abstract

We previously identified mutations in the Lpin1 gene, encoding lipin-1, as the underlying cause of lipodystrophy in the fatty liver dystrophy (fld) mutant mouse. Lipin-1 is normally expressed at high levels in adipose tissue and skeletal muscle, and deficiency in the fld mouse causes impaired adipose tissue development, insulin resistance, and altered energy expenditure. We also identified two additional lipin protein family members of unknown function, lipin-2 and lipin-3. Han et al. Triacylglycerol (TAG)3 plays a key role in metabolic homeostasis, serving as the major energy storage molecule that allows organisms to survive periods of food deprivation. The regulation of TAG storage is important in human disease because both excessive and inadequate fat storage is associated with dyslipidemia, insulin resistance, and diabetes (reviewed in Refs. 1-3). We previously characterized the fatty liver dystrophy mouse, a model of generalized lipodystrophy with impaired TAG storage in adipose tissue, insulin resistance, and increased susceptibility to atherosclerosis (4, 5). Lipodystrophy in the fld mouse results from mutation in the Lpin1 (lipin-1) gene, the founding member of a family of three genes of previously unknown function (6). Genes for lipin-1, lipin-2, and lipin-3 occur in mammals and other vertebrates, whereas a single lipin gene ortholog can be detected in evolutionarily distant organisms including fruit fly, nematode, plants, and yeast (6). This suggests a fundamental function for lipin that is conserved from single celled eukaryotes to mammals.In the mouse, lipin-1 is expressed at high levels in adipose tissue and skeletal muscle, consistent with a role in lipid metabolism in these tissues. Indeed, adipocytes in lipin-1-deficient mice fail to accumulate TAG and do not develop mature adipocyte function (7). By contrast, transgenic mice with enhanced lipin-1 expression in adipocytes accumulate more TAG per cell and are prone to obesity (7-9). Furthermore, lipin-1 expression levels are reduced in adipose tissue of human lipodystrophic patients concomitantly with reduced fat mass (10). A role for lipin-1 in muscle metabolism is suggested by increased energy expenditure and fatty acid oxidation in the muscle of lipin-1-deficient mice and the opposite effects in muscle-specific lipin-1 transgenic mice (8). Thus, alterations in lipin-1 expression levels in either adipose tissue or skeletal muscle produce important physiological effects on energy storage and expenditure.In mammalian cells, the de novo biosynthesis of TAG, PC, and phosphatidylethanolamine is catalyzed mainly through the glycerol phosphate pathway (11). Several enzymes in this pathway have been characterized, but not all of these have been identified at the molecular level. Among those for which a gene has not been isolated is the phosphatidate phosphohydrolase (phosphatase) type-1 that converts the PA formed from glycerol phosphate and lysoPA to DAG (12). There are two main types of PA phosphatase. The first is the type-1 activity (PAP1) that is ...

Identification of a Novel Cell-Penetrating Peptide from Human Phosphatidate Phosphatase LpIN3

“…LPIN3 is a human phosphatidate phosphatase, which has phosphatidate phosphatase type-1 (PAP1) activity and has a key role in glycerolipid metabolism (Donkor et al, 2007;Reue and Brindley, 2008). In the present study, we have identified a cell-penetrating amino acid sequence from LPIN3 and proved its delivery efficiency in vitro and in vivo.…”

“…LPINs are phosphatidate phosphatases that have multiple roles in the regulation of lipid metabolism and cell signaling (Donkor et al, 2007;Reue and Brindley, 2008). Most previous studies about LPINs involved lipid biosynthesis and its related roles in adipose tissue or, more recently, in macrophages (Valdearcos et al, 2011).…”

Identification of the transcript isoforms and expression characteristics for chicken Lpin1

“…LPIN1 is a PAP1 enzyme, which is required in the de novo biosynthesis of TG, phosphatidylcholine and phosphatidylethanolamine (Donkor et al, 2007). Here chicken Lpin1 ORF was cloned and its conservative elements were revealed.…”

“…First, LPIN1, as well as the related LPIN2 and LPIN3 proteins, acts as Mg 21 -dependent phosphatidate phosphatase type-1 (PAP1) enzymes, which catalyze a key step in the synthesis of glycerolipids (Han et al, 2006;Donkor et al, 2007;Harris et al, 2007). Second, Lpin1 can also act as a transcriptional coactivator.…”

Endoplasmic reticulum stress suppresses lipin-1 expression in 3T3-L1 adipocytes

“…Three lipin family genes including lipin-1, lipin-2, and lipin-3 have been found, and exhibit distinct tissue-specific expression patterns [2]. In adipocytes, lipin-1 is expressed at high levels, whereas lipin-2 is presented at low levels in mice [2].…”