Lipin proteins and metabolic homeostasis
2008; Elsevier BV; Volume: 50; Linguagem: Inglês
10.1194/jlr.r800052-jlr200
ISSN1539-7262
AutoresKaren Reue, Jennifer R. Dwyer,
Tópico(s)Endoplasmic Reticulum Stress and Disease
ResumoThe lipin protein family, consisting of three members, was first identified early this century. In the last few years, the lipin proteins have been shown to have important roles in glycerolipid biosynthesis and gene regulation, and mutations in the corresponding genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. Here, we review some of the progress toward elucidating the molecular and physiological functions of the lipin proteins. The lipin protein family, consisting of three members, was first identified early this century. In the last few years, the lipin proteins have been shown to have important roles in glycerolipid biosynthesis and gene regulation, and mutations in the corresponding genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. Here, we review some of the progress toward elucidating the molecular and physiological functions of the lipin proteins. THE LIPIN PROTEIN FAMILYThe lipin protein family consists of three members, lipin-1, lipin-2, and lipin-3. The founding member of the family, lipin-1, was identified via positional cloning as the mutated gene product in the fatty liver dystrophy (fld) mouse (1Péterfy 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: 121-124Crossref PubMed Scopus (463) Google Scholar). The name of the mutation refers to the occurrence of fatty liver and hypertriglyceridemia during the neonatal period, and peripheral neuropathy, which progresses throughout adulthood (2Langner C.A. Birkenmeier E.H. Schotz O.Ben-Zeev, M.C. Sweet H.O. Davisson M.T. Gordon J.I. 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: 7994-8003Abstract Full Text PDF PubMed Google Scholar, 3Langner C.A. Birkenmeier E.H. Roth K.A. Bronson R.T. Gordon J.I. 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: 11955-11964Abstract Full Text PDF PubMed Google Scholar). In addition, these mice are lipodystrophic, develop insulin resistance, and have increased susceptibility to atherosclerosis (4Reue K. Xu P. Wang X.P. Slavin B.G. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene.J. Lipid Res. 2000; 41: 1067-1076Abstract Full Text Full Text PDF PubMed Google Scholar). Lipin-1 is expressed in a variety of tissues, with the most prominent expression in adipose tissue, skeletal muscle, and testis (1Péterfy 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: 121-124Crossref PubMed Scopus (463) Google Scholar). Two lipin-1 protein isoforms are generated by alternative mRNA splicing, giving rise to proteins with predicted sizes of ∼98 and 102 kDa (5Huffman T.A. Lawrence Jr., I.Mothe-Satney, and J.C. Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin.Proc. Natl. Acad. Sci. USA. 2002; 99: 1047-1052Crossref PubMed Scopus (185) Google Scholar, 6Péterfy M. Phan J. Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Interestingly, lipin-1 protein can localize to either the cytoplasm or the nucleus (6Péterfy M. Phan J. Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar), which may be related to the dual roles of the protein (described below).The genes for lipin-2 and lipin-3 were identified by similarity of their predicted protein sequence to lipin-1 (1Péterfy 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: 121-124Crossref PubMed Scopus (463) Google Scholar). In addition, single lipin orthologs were identified in invertebrates, plasmodia, and yeast, and two lipin orthologs are present in plants. All lipin proteins exhibit two regions of especially high sequence conservation located in the N- and C-terminal protein regions, known as the N-LIP and C-LIP domains, respectively. This review will principally focus on lipin-1, about which the most is known, with information about the other two lipin family members provided where available.MOLECULAR FUNCTION OF LIPIN PROTEINSLipin-1 has two recently discovered molecular functions. First, lipin-1 acts as a phosphatidate phosphatase (PAP) enzyme, which converts phosphatidate to diacylglycerol during triglyceride, phosphatidylcholine, and phosphatidylethanolamine biosynthesis (reviewed in Refs. 7Carman G.M. Han G.S. Phosphatidic acid phosphatase, a key enzyme in the regulation of lipid synthesis.J. Biol. Chem. 2009; 284: 2593-2597Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 8Reue K. Brindley D.N. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism.J. Lipid Res. 2008; 49: 2493-2503Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar and Brindley, this issue). Although PAP enzyme activity had been studied for more than 50 years, the molecular identity was a mystery until Han, Wu, and Carman (9Han G.S. Wu W.I. Carman G.M. The Saccharomyces cerevisiae Lipin homolog is a Mg2+-dependent phosphatidate phosphatase enzyme.J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar) purified the enzyme from the yeast Saccharomyces cerevisiae and obtained peptide sequence that identified it as the yeast lipin ortholog. The PAP enzyme activity requires a DxDxT motif located in the C-LIP domain (see Fig. 1).After identification of the yeast PAP enzyme, PAP activity was subsequently demonstrated for all three mammalian lipin proteins, with lipin-1 having the highest specific activity (10Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 11Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1.J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). In the presence of elevated fatty acid levels within the cell, lipin proteins translocate from the cytosol to the endoplasmic reticulum membrane, where they encounter phosphatidic acid and catalyze its conversion to diacylglycerol (8Reue K. Brindley D.N. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism.J. Lipid Res. 2008; 49: 2493-2503Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). The three lipin genes have a distinct, but overlapping, tissue distribution (10Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar), suggesting that each may be responsible for the PAP activity in a specific set of tissues. As determined in tissues from the fld mouse, lipin-1 accounts for all of the PAP activity in adipose tissue and skeletal muscle, but only part of the activity in liver, heart, kidney, and brain (10Donkor J. Sariahmetoglu M. Dewald J. Brindley D.N. Reue K. Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.J. Biol. Chem. 2007; 282: 3450-3457Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 11Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1.J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar), and lipin-2 and/or lipin-3 may be active in these tissues.In addition to cytosolic localization, all of the mammalian lipin proteins possess a putative nuclear localization signal. It has been demonstrated that lipin-1 can localize to the nucleus in adipocytes (6Péterfy M. Phan J. Reue K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis.J. Biol. Chem. 2005; 280: 32883-32889Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar) and hepatocytes (12Bou Khalil M. Sundaram M. Zhang H.Y. Links P.H. Raven J.F. Manmontri B. Sariahmetoglu M. Tran K. Reue K. Brindley D.N. al et The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.J. Lipid Res. 2009; 50: 47-58Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar), and subcellular localization may be influenced by protein phosphorylation (11Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1.J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). The role of nuclear lipin-1 may be related to its function as a transcriptional coactivator. Finck et al. (13Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence Jr., J.C. Kelly D.P. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway.Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar) have shown that lipin-1 is required for the activation of hepatic fatty acid oxidation genes during fasting conditions. Lipin-1 directly interacts with the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α (PGC-1α) in a complex that modulates fatty acid oxidation gene expression. Lipin-1 coactivator activity requires an LxxIL sequence motif within the C-LIP domain (Fig. 1). These studies established a key role for lipin-1 in hepatic gene expression during fasting, but it is not clear whether lipin-1 coactivator activity has a physiological role in other tissues nor whether the other lipin family members exhibit similar activity.The recent elucidation of lipin-1 PAP and coactivator activities has provided new insight into the biological functions of lipin-1. One approach to understanding lipin-1 physiological function has been to study the effects of lipin-1 deficiency or enhanced lipin-1 expression using mouse models. As summarized below and in Fig. 2, lipin-1 has a unique physiological role in lipid homeostasis in tissues, including adipose tissue, skeletal muscle, liver, and peripheral nerve.Fig. 2Physiological effects of lipin-1 deficiency or enhanced expression. Summary of lipin-1 effects on metabolism in tissues shown. Characteristics shown in the left column are derived from studies in the lipin-1-deficient fld mouse or lipin-1-deficient human subjects (denoted by *). Characteristics shown in the right column are derived from studies of adipose-specific lipin-1 transgenic mice (adipose), muscle-specific lipin-1 transgenic mice (muscle), or from lipin-1 overexpression in liver via adenovirus (liver). See text for primary references.View Large Image Figure ViewerDownload Hi-res image Download (PPT)LIPIN PROTEINS AND ADIPOGENESISThe lipodystrophy in lipin-1-deficient mice is characterized by the presence of immature adipocytes that fail to store lipid or express mature adipocyte markers (4Reue K. Xu P. Wang X.P. Slavin B.G. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene.J. Lipid Res. 2000; 41: 1067-1076Abstract Full Text Full Text PDF PubMed Google Scholar). The lack of triglyceride storage in adipocytes from these mice can be attributed in large part to the deficiency in PAP activity, which is responsible for lipid synthesis in mature adipocytes. However, lipin-1-deficient cells exhibit additional defects in adipocyte differentiation. Lipin-1-deficient cells and adipose tissue fail to induce the key adipogenic transcription factor, PPARγ, and its target genes and instead express high levels of preadipocyte factor-1, an inhibitor of adipogenesis (14Phan J. Reue M.Péterfy, and K. Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Complementation of lipin-1-deficient preadipocytes with a retroviral vector expressing PPARγ partially rescues differentiation, suggesting that there is a requirement for lipin-1 at early stages of adipogenesis to facilitate PPARγ expression.Lipin-2 may also have a role in adipogenesis. Whereas lipin-1 is the predominant lipin in adipose tissue and its expression increases during differentiation of the 3T3-L1 adipocyte cell line, lipin-2 protein can be detected in preadipocytes but diminishes during differentiation (15Grimsey N. Han G.S. Rochford L.O'Hara, J.J. Carman G.M. Siniossoglou S. Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2.J. Biol. Chem. 2008; 283: 29166-29174Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). The fact that lipin-2 cannot compensate for lipin-1 function in adipose tissue of fld mice indicates that the two proteins serve different roles and may suggest that lipin-2 provides a regulatory function during adipogenesis.LIPIN-1, OBESITY, AND INSULIN SENSITIVITYWhile lipin-1 deficiency produces lipodystrophy in the mouse, enhanced lipin-1 expression in either adipose tissue or skeletal muscle promotes obesity (16Phan J. Reue K. Lipin, a lipodystrophy and obesity gene.Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). On a high-fat diet, both adipose tissue and muscle-specific lipin-1 transgene expression induce more rapid weight gain than in nontransgenic mice by 2-fold (adipose transgenic) or 4-fold (muscle transgenic), despite equivalent food intake. However, the mechanism for the obesity and the resulting effects on glucose homeostasis differ depending on whether lipin-1 expression is enhanced in adipose tissue or in muscle.The muscle-specific lipin-1 transgenic mice exhibit reduced energy expenditure and develop insulin resistance (16Phan J. Reue K. Lipin, a lipodystrophy and obesity gene.Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). The insulin resistance in these mice is presumably secondary to the obesity and/or increased PAP activity leading to triglyceride accumulation and altered metabolism in muscle. In contrast, enhanced lipin-1 levels in adipose tissue lead to increased adipocyte triglyceride content but lower glucose and insulin levels than wild-type mice on both chow and high-fat diets (16Phan J. Reue K. Lipin, a lipodystrophy and obesity gene.Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). Importantly, studies in humans have revealed a similar positive correlation between lipin-1 expression levels in adipose tissue and insulin sensitivity. This is true in both obese subjects with normal or impaired glucose tolerance (17Suviolahti E. Reue K. Cantor R.M. Phan J. Gentile M. Naukkarinen J. Oksanen A.Soro-Paavonen, L. Kaprio J. Rissanen A. al et Cross-species analyses implicate Lipin 1 involvement in human glucose metabolism.Hum. Mol. Genet. 2006; 15: 377-386Crossref PubMed Scopus (86) Google Scholar, 18Yao-Borengasser A. Rasouli N. Varma V. Miles L.M. Phanavanh B. Starks T.N. Phan J. III H.J. Spencer McGehee Jr., R.E. Reue K. al et Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation.Diabetes. 2006; 55: 2811-2818Crossref PubMed Scopus (88) Google Scholar) and in healthy young men (19Donkor J. Sparks L.M. Xie H. Smith S.R. Reue K. 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: 233-239Crossref PubMed Scopus (57) Google Scholar). It is possible that lipin-1 may promote efficient incorporation of fatty acids into adipocyte triglycerides, thereby preventing lipid deposition in other tissues where they could compromise insulin action (20Unger R.H. Lipotoxic diseases.Annu. Rev. Med. 2002; 53: 319-336Crossref PubMed Scopus (835) Google Scholar). Additionally, in human adipocytes, lipin-1 expression levels are correlated with glucose transporter 4 expression, which may increase glucose uptake (21van 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: 201-206Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar), and with expression of PPARα and fatty acid oxidation genes, which may prevent fatty acid accumulation (19Donkor J. Sparks L.M. Xie H. Smith S.R. Reue K. 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: 233-239Crossref PubMed Scopus (57) Google Scholar). Interestingly, lipin-1 expression is induced in adipocytes by insulin-sensitizing drugs such as thiazolidinediones and harmine (18Yao-Borengasser A. Rasouli N. Varma V. Miles L.M. Phanavanh B. Starks T.N. Phan J. III H.J. Spencer McGehee Jr., R.E. Reue K. al et Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferator-activated receptor gamma activation.Diabetes. 2006; 55: 2811-2818Crossref PubMed Scopus (88) Google Scholar, 22Waki H. Park K.W. Mitro N. Pei L. Damoiseaux R. Wilpitz D.C. Reue K. Saez E. Tontonoz P. The small molecule harmine is an anti-diabetic cell-type specific regulator of PPARg expression.Cell Metab. 2007; 5: 357-370Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar).In addition to the connection between lipin-1 and insulin sensitivity discussed above, insulin induces phosphorylation of lipin-1 at multiple sites (5Huffman T.A. Lawrence Jr., I.Mothe-Satney, and J.C. Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin.Proc. Natl. Acad. Sci. USA. 2002; 99: 1047-1052Crossref PubMed Scopus (185) Google Scholar, 11Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1.J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). Phosphorylation does not appear to alter the PAP-specific activity but rather to shift the localization toward the cytosolic rather than microsomal compartment (11Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence Jr., J.C. Insulin controls subcellular localization and multisite phosphorylation of the phosphatidic acid phosphatase, lipin 1.J. Biol. Chem. 2007; 282: 277-286Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar), potentially altering the proportion of lipin-1 that is available to catalyze the PAP reaction at the microsomal membrane. Studies in yeast have identified a specific phosphatase that acts on yeast lipin, and the mammalian counterpart of this phosphatase, known as Dullard, acts on mammalian lipin-1 (23Kim Y. Gentry M.S. Harris T.E. Wiley S.E. Lawrence Jr., J.C. Dixon J.E. A conserved phosphatase cascade that regulates nuclear membrane biogenesis.Proc. Natl. Acad. Sci. USA. 2007; 104: 6596-6601Crossref PubMed Scopus (112) Google Scholar, 24Santos-Rosa H. Leung J. Grimsey N. Siniossoglou S.Peak-Chew, and S. The yeast lipin Smp2 couples phospholipid biosynthesis to nuclear membrane growth.EMBO J. 2005; 24: 1931-1941Crossref PubMed Scopus (288) Google Scholar). Although the physiological significance of lipin protein phosphorylation is not yet fully understood, it is likely to represent an important mechanism for rapid modulation of lipin-1 compartmentalization and/or activity in response to insulin and other metabolic stimuli.LIPIN-1 AND PERIPHERAL NERVE FUNCTIONThe lipodystrophy in lipin-1-deficient mice is accompanied by severe peripheral neuropathy (3Langner C.A. Birkenmeier E.H. Roth K.A. Bronson R.T. Gordon J.I. 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: 11955-11964Abstract Full Text PDF PubMed Google Scholar). It is now clear that lipin-1 deficiency causes a lack of PAP activity in the fat pads that constitute the bulk of the epineurium in adult nerve, as well as in Schwann cells themselves (25Verheijen M.H. Chrast R. Burrola P. Lemke G. Local regulation of fat metabolism in peripheral nerves.Genes Dev. 2003; 17: 2450-2464Crossref PubMed Scopus (141) Google Scholar). Elegant studies of a Schwann cell-specific, lipin-1-deficient mouse demonstrated that lack of PAP activity in these cells is sufficient to cause peripheral neuropathy associated with myelin degradation and attenuated nerve conduction velocity (26Nadra K. Charles A.S. de Preux Medard J.J. Hendriks W.T. Han G.S. Gres S. Carman G.M. Verheijen J.S. Saulnier-Blache, M.H. Chrast R. Phosphatidic acid mediates demyelination in Lpin1 mutant mice.Genes Dev. 2008; 22: 1647-1661Crossref PubMed Scopus (105) Google Scholar). Furthermore, the accumulation of phosphatidate, the substrate for PAP, is responsible for eliciting aberrant signaling through the MEK/Extracellular signal-related kinase pathway, leading to dedifferentiation and proliferation of Schwann cells. These results raise the intriguing possibility that other symptoms of lipin deficiency are related not only to the loss of PAP enzyme function, but also to the deleterious effects of phosphatidate accumulation within the cell (reviewed in Ref. 8Reue K. Brindley D.N. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism.J. Lipid Res. 2008; 49: 2493-2503Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar).LIPIN-1 AND HEPATIC LIPOPROTEIN SECRETIONIt has been known for decades that PAP activity in the liver is regulated in response to changing metabolic conditions. For example, hepatic PAP activity is diminished in diabetes and starvation conditions and is increased with glucocorticoids (reviewed in Ref. (8Reue K. Brindley D.N. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism.J. Lipid Res. 2008; 49: 2493-2503Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). All three lipin family members are expressed in hepatocytes, but their expression is regulated independently. Glucocorticoids specifically increase mRNA and protein levels of lipin-1, but not lipin-2 or lipin-3 (27Manmontri B. Sariahmetoglu M. Donkor J. Khalil M.B. Sundaram M. Yao Z. Reue K. Lehner R. Brindley D.N. Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically.J. Lipid Res. 2008; 49: 1056-1067Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 28Zhang P. Brindley L.O'Loughlin, D.N. Reue K. Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis.J. Lipid Res. 2008; 49: 1519-1528Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The effect of glucocorticoids on lipin-1 is enhanced by glucagon or cAMP and antagonized by insulin (27Manmontri B. Sariahmetoglu M. Donkor J. Khalil M.B. Sundaram M. Yao Z. Reue K. Lehner R. Brindley D.N. Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically.J. Lipid Res. 2008; 49: 1056-1067Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar).Recent studies have implicated lipin-1 in the synthesis and secretion of VLDL in liver. This function of lipin-1 has been investigated by modulating lipin-1 levels in cultured hepatocytes and in the mouse. Enhanced expression of lipin-1 in a rat hepatocyte cell line led to stimulation of triglyceride synthesis and secretion, while knockdown of endogenous lipin-1 expression decreased the secretion of newly synthesized triglycerides (12Bou Khalil M. Sundaram M. Zhang H.Y. Links P.H. Raven J.F. Manmontri B. Sariahmetoglu M. Tran K. Reue K. Brindley D.N. al et The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.J. Lipid Res. 2009; 50: 47-58Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Interestingly, deletion of the lipin-1 nuclear localization signal led to impaired association with the microsomal membranes and less effective induction of triglyceride synthesis. These results suggest that lipin-1 compartmentalization within hepatocytes may be a determinant of triglyceride synthesis and VLDL secretion.However, studies performed in vivo indicate that the relationship between lipin-1 and VLDL secretion is more complex than observed in a hepatocyte cell line. Hepatocytes isolated from adult fld mice were shown to secrete VLDL at increased rates compared with wild-type hepatocytes (29Chen Z. Gropler M.C. Norris J. Lawrence Jr., J.C. Harris T.E. Finck B.N. Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1738-1744Crossref PubMed Scopus (67) Google Scholar), suggesting that lipin-2 and/or lipin-3 are capable of promoting VLDL synthesis and secretion. On the other hand, mice treated with an adenovirus to increase lipin-1 expression in the liver exhibited reduced rates of VLDL secretion (29Chen Z. Gropler M.C. Norris J. Lawrence Jr., J.C. Harris T.E. Finck B.N. Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1738-1744Crossref PubMed Scopus (67) Google Scholar), in direct contrast to results obtained in vitro (12Bou Khalil M. Sundaram M. Zhang H.Y. Links P.H. Raven J.F. Manmontri B. Sariahmetoglu M. Tran K. Reue K. Brindley D.N. al et The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL.J. Lipid Res. 2009; 50: 47-58Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). Through the use of mutant lipin-1 molecules, this effect was shown to require lipin-1 transcriptional coactivator but not PAP enzyme function. Consistent with the results of lipin-1 adenovirus overexpression in the mouse, hepatic lipin-1 expression levels and VLDL secretion both increased in obese individuals following gastric bypass surgery (30Croce M.A. Eagon J.C. LaRiviere L.L. Korenblat K.M. Klein S. Finck B.N. Hepatic lipin 1beta expression is diminished in insulin-resistant obese subjects and is reactivated by marked weight loss.Diabetes. 2007; 56: 2395-2399Crossref PubMed Scopus (58) Google Scholar). Taken together, it appears that lipin proteins influence hepatic triglyceride synthesis and VLDL secretion, but at present, it is difficult to attribute effects solely to specific lipin family members and to distinguish the contributions of PAP versus coactivator activities.LIPIN-1 GENE MUTATIONS AND POLYMORPHISMS ASSOCIATED WITH DISEASEMutations affecting lipin-1 and lipin-2 cause human disease. While two distinct mutations in mouse Lpin1 cause lipodystrophy (1Péterfy 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: 121-124Crossref PubMed Scopus (463) Google Scholar) (Fig. 1), analysis of human lipodystrophic subjects has failed to detect causative mutations in the LPIN1 gene (31Cao H. Hegele R.A. Identification of single-nucleotide polymorphisms in the human LPIN1 gene.J. Hum. Genet. 2002; 47: 370-372Crossref PubMed Scopus (20) Google Scholar, 32Fawcett K.A. Grimsey N. Loos R.J. Wheeler E. Daly A. Soos M. Semple R. Syddall H. Cooper C. Siniossoglou S. al et Evaluating the role of LPIN1 variation on insulin resistance, body weight and human lipodystrophy in UK populations.Diabetes. 2008; 57: 2527-2533Crossref PubMed Scopus (40) Google Scholar). However, mutations in LPIN1 have been identified in patients with recurrent acute myoglobinuria in childhood (33Zeharia A. Shaag A. Houtkooper R.H. Hindi T. Lonlay P.de Erez G. Hubert L. Saada A. Keyzer Y.de Eshel G. al et Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.Am. J. Hum. Genet. 2008; 83: 489-494Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). Distinct inactivating mutations were detected in patients from several ethnic backgrounds and occur at dispersed locations throughout the lipin-1 prot
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