PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Curr Opin Lipidol. Author manuscript; available in PMC Jun 1, 2010.
Published in final edited form as:
PMCID: PMC2875192
NIHMSID: NIHMS193400

The Lipin Family: Mutations and Metabolism

Abstract

Purpose of review

The family of three lipin proteins act as phosphatidate phosphatase (PAP) enzymes required for glycerolipid biosynthesis, and also as transcriptional coactivators that regulate expression of lipid metabolism genes. The genes for lipin-1, lipin-2 and lipin-3 are expressed in key metabolic tissues, including adipose tissue, skeletal muscle, and liver, but the physiological functions of each member of the family have not been fully elucidated. Here we examine the most recent studies that provide information about the roles of lipin proteins in metabolism and human disease.

Recent findings

Recent studies have identified mutations that cause lipin-1 or lipin-2 deficiency in humans, leading to acute myoglobinuria in childhood or the inflammatory disorder Majeed syndrome, respectively. The effects of lipin-1 deficiency appear to include both the loss of glycerolipid building blocks and the accumulation of lipid intermediates that disrupt cellular function. Several studies have demonstrated that polymorphisms in the LPIN1 and LPIN2 genes are associated with metabolic disease traits, including insulin sensitivity, diabetes, blood pressure, and response to thiazolidinedione drugs. Furthermore, lipin-1 expression levels in adipose tissue and/or liver are positively correlated with insulin sensitivity. Studies of lipin-1 in adipocytes have shed some light on its relationship with insulin sensitivity.

Summary

Lipin-1 and lipin-2 are required for normal lipid homeostasis, and have unique physiological roles. Future studies, for example using engineered mouse models, will be required to fully elucidate their specific roles in normal physiology and disease.

Keywords: triglyceride, phosphatidic acid phosphatase, transcriptional coactivator, lipodystrophy, obesity, insulin resistance, myopathy

Introduction

It is clear from diseases such as obesity and lipodystrophy that the regulation of lipid storage is critical for metabolic homeostasis [1, 2]. Impaired and excessive triacylglycerol (TAG) storage in adipose tissue are both associated with inappropriate lipid accumulation in tissues such as liver and skeletal muscle, and impaired adipokine production. These, in turn, contribute to insulin resistance and dyslipidemia, key components of the metabolic syndrome [3]. It is therefore of interest to identify factors that influence lipid biosynthesis and storage, and determine how genetic variation in the activity of these factors contributes to metabolic dysfunction. In this review we will highlight recent studies on the mammalian lipin proteins, which function in TAG synthesis and metabolism in tissues such as adipose tissue, liver, and skeletal muscle. The role of the orthologous yeast protein has recently been described in excellent reviews [4, 5] and will not be discussed here.

The lipin protein family

The lipin gene family encodes the proteins lipin-1, lipin-2, and lipin-3. The Lpin1 gene was first isolated from the fatty liver dystrophy (fld) mutant mouse strain [6, 7], where lipin-1 deficiency was identified as the cause of lipodystrophy, insulin resistance, peripheral neuropathy, and neonatal fatty liver in these animals [8]. Lipin-1 is expressed as two protein isoforms, lipin-1α and lipin-1β, derived from the Lpin1 gene by alternative mRNA splicing [8, 9]. Lipin-2 and lipin-3 were identified based on 60% amino acid sequence similarity to lipin-1 [8]. Lipin family proteins are present in species ranging from mammals to yeast, and all have highly conserved regions known as the N-LIP and C-LIP domains, which are critical for protein function (see Fig. 1).

Fig. 1
Position of lipin protein functional motifs and naturally occurring mutations

The identification of lipin protein molecular function has been reviewed recently [4, 10]. The current understanding is that all of the mammalian lipin proteins are phosphatidate phosphatase (PAP) enzymes, which convert phosphatidate to diacylglycerol, and therefore act at a key step in the synthesis of TAG, phosphatidylcholine and phosphatidylethanolamine [1113]. Additionally, lipin-1 can localize to the nucleus [8, 14, 15], and is a component of a transcriptional complex with peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α) to regulate fatty acid metabolism in liver [16]. Amino acid motifs required for lipin-1 PAP activity (DIDGT) and transcriptional coactivator activity (LXXIL) reside in the C-LIP domain [12, 16] (see Fig. 1).

The three lipin genes each exhibit a unique pattern of tissue expression, suggesting independent physiological roles. Lipin-1 is expressed at highest levels in adipose tissue, skeletal muscle, and testis, and is also detected in liver, heart, brain, kidney, and other tissues [8]. Using tissues from lipin-1 deficient fld mice, it was shown that lipin-1 accounts for virtually all of the PAP activity in adipose tissue, skeletal muscle, and heart, but that other proteins may contribute to activity in liver [11, 13]. The role of lipin-1 in adipose tissue has been studied extensively and found to be required both for expression of key adipogenic genes during adipocyte differentiation, and for TAG accumulation [15, 17]. A role for lipin-1 in skeletal muscle has also been demonstrated through studies of muscle-specific lipin-1 transgenic mice, which exhibit reduced fatty acid oxidation in muscle and reduced energy expenditure, becoming obese [18]. Lipin-2 is expressed in many tissues including liver, kidney, brain, and lung, whereas lipin-3 is detected at low levels in liver and other visceral tissues that have been tested [11]. Recent studies have made use of naturally occurring mutations in lipin-1 and lipin-2 to further elucidate the roles of these proteins in vivo.

Lipin-1 gene mutations and disease

It was previously shown that two naturally occurring mutations in the mouse Lpin1 gene (gene rearrangement leading to a null allele, and a Gly84Arg substitution in the N-LIP domain) cause the fatty liver dystrophy phenotype (Fig. 1) [8]. Recently, the first mutations causing lipin-1 deficiency in humans have been documented (Fig. 1). Homozygous or compound heterozygous LPIN1 mutations cause recurrent muscle pain, weakness, and myoglobinuria in childhood [19]. Nonsense mutations that lead to lipin-1 deficiency were detected in subjects of various ethnic backgrounds. All patients presented before age 7 with episodes of myoglobinuria. Curiously, unlike lipin-1 deficient mice, patients with LPIN1 mutations do not appear to have lipodystrophy, although they have thus far been examined only in childhood. The basis for the species difference in symptoms resulting from lipin-1 deficiency is not clear. It has been observed that lipin-2 is expressed in human adipose tissue raising the possibility of compensation for lipin-1 deficiency [11]; however, studies in cultured mouse adipocytes indicate that lipin-2 cannot substitute for lipin-1 in adipocyte differentiation [17, 20].

In the same study reporting LPIN1 nonsense mutations, the authors identified a missense mutation (Pro610Ser) in the C-LIP domain in an individual with myopathy occurring after treatment with statin drugs [19]. Although it must be expanded to larger numbers of individuals, this observation raises interesting questions. Statin drugs are used worldwide to treat hypercholesterolemia, and a proportion of individuals develop mild (2–7%) or severe (0.5%) muscle pain and myopathy [21]. Statin drugs inhibit synthesis of the cholesterol precursor mevalonate, which is also a precursor of ubiquinone, a critical component of the mitochondrial electron transport chain. In rat muscle, lipin-1 expression is induced by acute exercise and may contribute to exercise-induced mitochondrial enzyme induction [22]. Further investigation will be necessary to establish whether reduced lipin-1 PAP activity sensitizes muscle to mitochondrial toxicity in response to statin treatment.

Lipin-2 mutations and disease

Homozygous and compound heterozygous LPIN2 mutations cause Majeed syndrome, a rare disorder characterized by recurrent osteomyelitis, cutaneous inflammation, and anemia [2325]. Several independent LPIN2 mutations have been described, including nonsense mutations and a missense mutation (Ser734Leu) in the C-LIP domain (Fig. 1). Several additional missense mutations in LPIN2 have been associated with psoriasis [26], suggesting that these lead to impaired, but not absent, lipin-2 function. Since lipin-2 expression has not been characterized in tissues such as bone, skin, and blood cells, the etiology of Majeed syndrome and psoriasis symptoms in these tissues is unclear at present.

Lipin gene expression levels and polymorphisms associated with metabolic traits

Previous studies in adipose tissue-specific lipin-1 transgenic mice suggested a positive relationship between lipin-1 levels in adipose tissue and whole body glucose tolerance, irrespective of body fat mass [18]. The improved glucose homeostasis with enhanced lipin-1 expression may reflect more efficient fatty acid trapping in adipose tissue due to increased PAP activity, and protection of other tissues from inappropriate lipid accumulation. Several recent studies have confirmed the relationship between adipose tissue lipin-1 levels and insulin sensitivity in humans. These include studies in lean and obese subjects with normal or impaired glucose tolerance [2729], in HIV-associated lipodystrophic subjects [27, 30], and in healthy young men [31]. In healthy young men, lipin-1 levels were also positively correlated with insulin-stimulated respiratory quotient, oxygen consumption during exercise, and the expression of genes involved in fatty acid oxidation, including PPARα [31].

In a unique study in which lipin-1 levels were monitored before and after gastric bypass surgery of extremely obese subjects, lipin-1β mRNA levels in liver and adipose tissue were increased in parallel with improved insulin sensitivity following marked weight loss [32]. Hepatic lipin-1β mRNA levels were also correlated with PGC-1α expression, suggesting that the downregulation of these proteins may contribute to reduced insulin sensitivity in obesity. Patients with polycystic ovary syndrome (PCOS), a condition associated with insulin resistance, were shown to have reduced lipin-1β expression in both visceral and subcutaneous adipose tissue, which was independent of body mass index [33]. Greater levels of lipin-1β were detected in subcutaneous compared to visceral fat, and may be a determinant of the greater capacity for expansion and TAG storage in this depot.

LPIN1 polymorphisms and haplotypes may confer interindividual variation in lipin-1 action and have been associated with several components of the metabolic syndrome. LPIN1 polymorphisms have been associated with body mass index [28, 34, 35], insulin levels [28, 36], resting metabolic rate [36], and responsiveness to thiazolidinediones drugs [37]. A common LPIN1 haplotype was associated with risk for metabolic syndrome, while two less common haplotypes appeared to have a protective effect and to associate with low systolic blood pressure and hemoglobin A1C levels [35, 38]. However, in a study of UK populations, no associations were detected between common LPIN1 variants and insulin levels, nor were LPIN1 mutations detected in 23 lipodystrophic patients [34]. Overall, the studies to date indicate that LPIN1 gene polymorphisms may influence several traits related to the metabolic syndrome, although this may differ among populations. In the pig, Lpin1 polymorphisms have been associated with percent leaf fat and intramuscular fat [39]. Although not widely studied thus far, a LPIN2 gene polymorphism has been associated with diabetes risk [40].

Mechanisms of disease in lipin-1 dysfunction

Recent studies in both lipin-1 deficient mice and humans suggest that deleterious effects of PAP deficiency in tissues such as peripheral nerve, adipose tissue and muscle may be attributable to both the lack of PAP products and the accumulation of phosphatidate substrate. In an elegant study designed to evaluate the biochemical basis for the demyelination of peripheral nerves in fld mice, Nadra and colleagues demonstrated that lipin-1 PAP deficiency causes phosphatidate to accumulate in adipose tissue and peripheral nerve [41]. This, in turn, leads to activation of the MEK-Erk signaling pathway in Schwann cells and demyelination. Along the same lines, muscle tissue from one lipin-1 deficient human subject was shown to have elevated levels of lysophosphatidate, phosphatidate, and lysophospholipids [19]. Normally, intracellular levels of phosphatidate are tightly controlled, and disturbances may lead to inappropriate modulation of signaling cascades, oxidative processes, cAMP degradation, protein and lipid phosphorylation, and membrane function [42].

A hallmark feature of lipin-1 deficiency in the fld mouse is the occurrence of a fatty liver and hypertriglyceridemia during the neonatal period [6], suggesting that lipin-1 PAP activity is not required for hepatic TAG synthesis and secretion. In support of this, a recent study demonstrates that lipin-1β overexpression decreases hepatic very low density lipoprotein (VLDL) TAG secretion [43]. Further, using mutant recombinant lipin-1β proteins, it was shown that PAP activity is not required for the suppression of TAG synthesis, whereas the LXXIL motif conferring transcriptional coactivator activity and PPARα binding is required. A separate study, performed in hepatocytes, demonstrated that lipin-1α or lipin-1β overexpression increases glycerol-labeled lipid secretion, and decreases the degradation of the predominant VLDL protein, apolipoprotein B [14]. The lipin-1 nuclear localization signal was shown to be required for protein localization to microsomal membranes and PAP activity. Together, the two studies indicate a role for lipin-1 in the regulation of VLDL-TAG synthesis and/or secretion, but suggest that lipin-1 PAP and coactivator activities may have distinct roles. An additional complication is the presence of substantial lipin-2 in liver, which likely affects hepatic TAG synthesis ([11, 44]; discussed in a later section).

Regulation of lipin levels and activity

It was previously shown that lipin-1 is phosphorylated at several sites in response to insulin and amino acids, and dephosphorylated in response to oleic acid or epinephrine [9, 13, 45]. Phosphorylation appears to influence lipin-1 activity by modulating subcellular localization [13]. In the past year, several studies have focused on delineating the regulation of lipin-1 gene expression. All three lipin genes are expressed in liver, and it has been known for decades that PAP activity in liver is induced by glucocorticoid treatment, which increases its capacity to store TAG for subsequent assembly into lipoproteins or use in beta-oxidation (reviewed in [10]). It was recently shown that dexamethasone increases lipin-1, but not lipin-2 or lipin-3, mRNA, and this resulted in increased lipin-1 protein synthesis and PAP activity [44]. The glucocorticoid stimulatory effect was enhanced by cAMP or glucagon, and diminished by insulin. Dexamethasone also induces lipin-1 expression and PAP activity during adipocyte differentiation, which is mediated by glucocorticoid receptor binding to a DNA sequence upstream of Lpin1 [46]. Lipin-1 gene transcription during adipocyte differentiation is also regulated by binding of CAAT/enhancer binding protein α in the Lpin1 upstream region [47]. Lipin-1 then acts in combination with PPARγ to promote expression of adipocyte genes, including glucose transporter 4 (Glut4) [47].

Consistent with the correlation between lipin-1 levels and insulin sensitivity, lipin-1 expression is induced in adipose tissue by the insulin-sensitizing thiazolidinediones and harmine [29, 48, 49]. Thiazolidinediones also increase PAP activity, with greatest effect on subcutaneous compared to visceral adipose tissue [48]. This may contribute to the fat redistribution that is observed in conjunction with insulin sensitization in response to thiazolidinediones. Several studies have shown that lipin-1 expression is correlated with Glut4 expression [33, 47, 50], providing a plausible mechanism for the relationship between thiazolidinediones, lipin-1 expression, and insulin sensitivity.

Other stimuli repress lipin-1 expression. Lipin-1 expression is inhibited by estrogen in the uterus and liver, suggesting a potential role for lipin-1 in reproductive biology [51]. Consistent with this, elevated estrogen levels and impaired fertility in non-obese diabetic mice are associated with depletion of lipin-1 in the uterus and liver, a state that can be reversed by insulin administration [51]. Lipin-1 expression is repressed in adipocytes by activation of toll-like receptors TLR4 and TLR2 by lipopolysaccharide and zymosan, respectively [52]. These effects appear to be mediated by inflammatory cytokines such as TNFα and IL-1, and it is proposed that lipin-1 repression may contribute to the reduced fat storage that accompanies infection and inflammation.

The regulation of lipin-2 has recently been examined in adipocytes and liver. During differentiation of 3T3-L1 adipocytes, lipin-1 and lipin-2 expression occurs in a reciprocal manner, with lipin-2 protein detected in preadipocytes, but falling dramatically after 24 hours of differentiation, after which lipin-1 protein is detectable [20]. Lipin-2 cannot substitute for lipin-1 in adipocyte differentiation, indicating that the two proteins do not have redundant functions in adipocytes [20]. Lipin-2 is expressed at highest levels in liver, suggesting a role as a key PAP in this tissue [11]. In the liver, lipin-2 protein content was increased in neonatal lipin-1 deficient fld mice, as well as in response to food deprivation or obesity [53]. Inhibition of lipin-2 in hepatocytes by RNAi reduced PAP activity, consistent with a role for this lipin as an important PAP enzyme in liver [53].

Conclusion

The lipin proteins modulate intracellular lipid levels through roles in lipid synthesis and in fatty acid metabolism. The study of mouse and human mutations has established that lipin-1 and lipin-2 each have a unique physiological function that cannot be substituted by the other family members. Future studies utilizing engineered mouse mutations may be a useful strategy to better define normal physiological function of each lipin protein, disease mechanisms, and the roles of enzymatic and transcriptional coactivator activities.

Acknowledgments

This work was supported by P01 HL90553 and P01 HL28481.

References and recommended reading

1. Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350:1220–34. [PubMed]
2. Smyth S, Heron A. Diabetes and obesity: the twin epidemics. Nat Med. 2006;12:75–80. [PubMed]
3. Lusis AJ, Attie AD, Reue K. Metabolic syndrome: from epidemiology to systems biology. Nat Rev Genet. 2008;9:819–30. [PMC free article] [PubMed]
4. Carman GM, Han GS. Phosphatidic acid phosphatase, a key enzyme in the regulation of lipid synthesis. J Biol Chem. 2009;284:2593–2597. [PubMed]
5. Carman GM, Henry SA. Phosphatidic acid plays a central role in the transcriptional regulation of glycerophospholipid synthesis in Saccharomyces cerevisiae. J Biol Chem. 2007;282:37293–37297. [PMC free article] [PubMed]
6. Langner CA, Birkenmeier EH, Ben-Zeev O, et al. The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. J Biol Chem. 1989;264:7994–8003. [PubMed]
7. Langner CA, Birkenmeier EH, Roth KA, et al. Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. J Biol Chem. 1991;266:11955–64. [PubMed]
8. Péterfy M, Phan J, Xu P, Reue K. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet. 2001;27:121–4. [PubMed]
9. Huffman TA, Mothe-Satney I, Lawrence JC., Jr Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci U S A. 2002;99:1047–52. [PubMed]
10. Reue K, Brindley DN. Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. J Lipid Res. 2008;49:2493–2503. [PubMed]
11. Donkor J, Sariahmetoglu M, Dewald J, et al. Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns. J Biol Chem. 2007;282:3450–3457. [PubMed]
12. Han GS, Wu WI, Carman GM. The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme. J Biol Chem. 2006;281:9210–8. [PMC free article] [PubMed]
13. Harris TE, Huffman TA, Chi A, et al. Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1. J Biol Chem. 2007;282:277–86. [PubMed]
14 * Bou Khalil M, Sundaram M, Zhang HY, et al. The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic very low density lipoproteins. J Lipid Res. 2008;50:47–58. A study demonstrating a role for lipin-1 in hepatocyte TAG secretion and intracellular apolipoprotein B turnover. [PubMed]
15. Péterfy M, Phan J, Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J Biol Chem. 2005;280:32883–9. [PubMed]
16. Finck BN, Gropler MC, Chen Z, et al. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab. 2006;4:199–210. [PubMed]
17. Phan J, Péterfy M, Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro. J Biol Chem. 2004;279:29558–64. [PubMed]
18. Phan J, Reue K. Lipin, a lipodystrophy and obesity gene. Cell Metab. 2005;1:73–83. [PubMed]
19 ** Zeharia A, Shaag A, Houtkooper RH, et al. Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood. Am J Hum Genet. 2008;83:1–6. The first report of mutations causing lipin-1 deficiency in humans, revealing an unexpected myoglobinuria phenotype and accumulation of lipid intermediates in muscle. [PubMed]
20 ** Grimsey N, Han GS, O’Hara L, et al. Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2. J Biol Chem. 2008;283:29166–29174. Demonstration that lipin-1 and lipin-2 proteins are expressed in a reciprocal fashion in differentiating adipocytes, indicating a previously undetected role for lipin-2 in adipocytes. [PMC free article] [PubMed]
21. Sirvent P, Mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol. 2008;8:333–338. [PubMed]
22. Higashida K, Higuchi M, Terada S. Potential role of lipin-1 in exercise-induced mitochondrial biogenesis. Biochem Biophys Res Commun. 2008;374:587–91. [PubMed]
23. El-Shanti HI, Ferguson PJ. Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res. 2007;462:11–19. [PubMed]
24. Ferguson PJ, Chen S, Tayeh MK, et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome) J Med Genet. 2005;42:551–7. [PMC free article] [PubMed]
25. Majeed HA, Al-Tarawna M, El-Shanti H, et al. The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr. 2001;160:705–10. [PubMed]
26. Milhavet F, Cuisset L, Hoffman HM, et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat. 2008;29:803–8. [PubMed]
27. Miranda M, Chacon MR, Gomez J, et al. Human subcutaneous adipose tissue LPIN1 expression in obesity, type 2 diabetes mellitus, and human immunodeficiency virus--associated lipodystrophy syndrome. Metabolism. 2007;56:1518–26. [PubMed]
28. Suviolahti E, Reue K, Cantor RM, et al. Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism. Hum Mol Genet. 2006;15:377–86. [PubMed]
29. Yao-Borengasser A, Rasouli N, Varma V, et al. Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation. Diabetes. 2006;55:2811–8. [PubMed]
30. Lindegaard B, Larsen LF, Hansen AB, et al. Adipose tissue lipin expression levels distinguish HIV patients with and without lipodystrophy. Int J Obes. 2006;31:449–456. [PubMed]
31 * Donkor J, Sparks LM, Xie H, et al. Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men. J Clin Endocrinol Metab. 2008;93:233–9. First study to examine variations in lipin-1 gene expression in adipose tissue of young, healthy individuals detected correlations with insulin sensitivity, energy metabolism, and oxidative gene expression. [PubMed]
32. Croce MA, Eagon JC, LaRiviere LL, et al. Hepatic lipin 1beta expression is diminished in insulin-resistant obese subjects and is reactivated by marked weight loss. Diabetes. 2007;56:2395–9. [PubMed]
33 * Mlinar B, Pfeifer M, Vrtacnik Bokal E, et al. Decreased lipin 1{beta} expression in visceral adipose tissue is associated with insulin resistance in polycystic ovary syndrome. Eur J Endocrinol. 2008;159:833–839. Demonstration that reduced lipin-1β expression levels in subcutaneous adipose tissue of PCOS patients correlate negatively with insulin resistance and triglyceride levels, and positively with glucose transporter 4 expression. [PubMed]
34 * Fawcett KA, Grimsey N, Loos RJ, et al. Evaluating the role of LPIN1 variation on insulin resistance, body weight and human lipodystrophy in UK populations. Diabetes. 2008;57:2527–2533. Demonstration that LPIN1 mutations are not a common cause of lipodystrophy. [PMC free article] [PubMed]
35 ** Wiedmann S, Fischer M, Koehler M, et al. Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans. Diabetes. 2008;57:209–17. Identification of LPIN1 haplotypes that are either protective or associated with several traits of the metabolic syndrome, including blood pressure, obesity, diabetes, hemoglobin A1c levels, and metabolic syndrome factor score. [PubMed]
36. Loos RJ, Rankinen T, Perusse L, et al. Association of lipin 1 gene polymorphisms with measures of energy and glucose metabolism. Obesity (Silver Spring) 2007;15:2723–32. [PubMed]
37 * Kang ES, Park SE, Han SJ, et al. LPIN1 genetic variation is associated with rosiglitazone response in type 2 diabetic patients. Mol Genet Metab. 2008;95:96–100. Report of a LPIN1 polymorphism that is associated with rosiglitazone-induced decreases in fasting and postprandial glucose and hemoglobin-A1c levels. [PubMed]
38 * Ong KL, Leung RY, Wong LY, et al. Association of a polymorphism in the lipin 1 gene with systolic blood pressure in men. Am J Hypertens. 2008;21:539–45. Association of systolic blood pressure in men with a LPIN1 polymorphism that forms an exonic splicing silencer sequence. [PubMed]
39. He XP, Xu XW, Zhao SH, et al. Investigation of Lpin1 as a candidate gene for fat deposition in pigs. Mol Biol Rep. 2008 [Epub ahead of print] [PubMed]
40. Aulchenko YS, Pullen J, Kloosterman WP, et al. LPIN2 is associated with type 2 diabetes, glucose metabolism, and body composition. Diabetes. 2007;56:3020–6. [PubMed]
41 ** Nadra K, de Preux Charles AS, Medard JJ, et al. Phosphatidic acid mediates demyelination in Lpin1 mutant mice. Genes Dev. 2008;22:1647–61. Schwann cell-specific Lpin1 ablation was sufficient to cause peripheral neuropathy in mice, and was associated with endoneurial accumulation of phosphatidate and activation of the MEK-Erk signaling pathway. [PubMed]
42. Andresen BT, Rizzo MA, Shome K, Romero G. The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade. FEBS Lett. 2002;531:65–68. [PubMed]
43 ** Chen Z, Gropler MC, Norris J, et al. Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion. Arterioscler Thromb Vasc Biol. 2008 Demonstration that the coactivator function of lipin-1 suppresses hepatic VLDL secretion rates, and that overexpression in liver improves insulin signaling in obese mice. [PMC free article] [PubMed]
44 * Manmontri B, Sariahmetoglu M, Donkor J, et al. Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically. J Lipid Res. 2008;49:1056–67. Identification of lipin-1 as the glucocorticoid responsive hepatic PAP activity, and demonstration that lipin-1, -2, and -3 are regulated independently in liver. [PubMed]
45. Kim Y, Gentry MS, Harris TE, et al. A conserved phosphatase cascade that regulates nuclear membrane biogenesis. Proc Natl Acad Sci U S A. 2007;104:6596–601. [PubMed]
46 * Zhang P, O’Loughlin L, Brindley DN, Reue K. Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis. J Lipid Res. 2008;49:1519–28. Identification of a regulatory element that binds glucocorticoid receptor and induces its expression in differentiating adipocytes and in conditions of high glucocorticoid levels in vivo. [PubMed]
47 ** Koh Y-K, Lee M-Y, Kim J-W, et al. Lipin1 is a key factor for the maturation and maintenance of adipocytes in the regulatory network with CCAAT/enhancer-binding protein a and peroxisome proliferator-activated receptor 2. J Biol Chem. 2008;50:34896–34906. Demonstration that lipin-1 is part of the regulatory network between C/EBPα and PPARγ during adipogenesis, and is directly regulated by binding of C/EBPα to a response element in the Lpin1 promoter. [PubMed]
48 * Festuccia WT, Blanchard P-G, Turcotte V, et al. Depot-specific effects of the PPAR agonist rosiglitazone on adipose tissue uptake and metabolism. J Lipid Res. 2009 Epub ahead of print (Feb. 9, 2009). Study describing rosiglitazone induction of lipin-1 mRNA and PAP activity to a greater level in subcutaneous than visceral adipose tissue, implicating increased PAP activity in the redistribution of adipose tissue in response to insulin-sensitizing PPARγ agonists. [PubMed]
49. Waki H, Park KW, Mitro N, et al. The small molecule harmine is an anti-diabetic cell-type specific regulator of PPARγ expression. Cell Metab. 2007;5:357–370. [PubMed]
50. van Harmelen V, Ryden M, Sjolin E, Hoffstedt J. A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport and GLUT4 expression. J Lipid Res. 2007;48:201–6. [PubMed]
51. Gowri PM, Sengupta S, Bertera S, Katzenellenbogen BS. Lipin1 regulation by estrogen in uterus and liver: implications for diabetes and fertility. Endocrinology. 2007;148:3685–93. [PubMed]
52 * Lu B, Lu Y, Moser AH, et al. LPS and proinflammatory cytokines decrease lipin-1 in mouse adipose tissue and 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab. 2008;295:E1502–9. Repression of adipose tissue lipin-1 mRNA expression in response to inflammatory stimuli, suggesting a mechanism for reduced fat storage in infection. [PubMed]
53 * Gropler MC, Harris TE, Hall AM, et al. Lipin 2 is a liver-enriched phosphatidate phosphohydrolase enzyme that is dynamically regulated by fasting and obesity in mice. J Biol Chem. 2009 Epub ahead of print (Jan. 10, 2009). Demonstration that hepatic lipin-2 protein levels are increased by lipin-1 deficiency, fasting, and obesity, suggesting an important contribution to liver PAP activity. [PubMed]