Mammalian lipin phosphatidic acid phosphatases in lipid synthesis and beyond: metabolic and inflammatory disorders
2019; Elsevier BV; Volume: 60; Issue: 4 Linguagem: Inglês
10.1194/jlr.s091769
ISSN1539-7262
Autores Tópico(s)Adipose Tissue and Metabolism
ResumoA deep understanding of the mechanisms that regulate cellular lipid storage and membrane content is necessary to elucidate human metabolic disorders such as obesity and fatty liver, and related diseases including type 2 diabetes and atherosclerosis. The mammalian lipin proteins (lipin 1, lipin 2, and lipin 3) are active in the synthesis of both the major storage lipid, triacylglycerol (TAG), and major membrane phospholipids (1Wang H. Airola M.V. Reue K. How lipid droplets “TAG” along: glycerolipid synthetic enzymes and lipid storage.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017; 1862: 1131-1145Crossref PubMed Scopus (62) Google Scholar, 2Coleman R.A. Mashek D.G. Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling.Chem. Rev. 2011; 111: 6359-6386Crossref PubMed Scopus (170) Google Scholar). The lipin proteins also regulate lipid intermediates that activate signaling nodes for diverse cellular processes (3Csaki L.S. Dwyer J.R. Fong L.G. Tontonoz P. Young S.G. Reue K. Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling.Prog. Lipid Res. 2013; 52: 305-316Crossref PubMed Scopus (93) Google Scholar). As a result, lipin proteins are involved in many cellular processes, including the regulation of lipid storage, lipoprotein synthesis, autophagy, inflammation, and gene expression. Here, we provide an overview of the mammalian lipins and their roles in normophysiology and disease. Due to space constraints, the reader is referred to other recent reviews on mammalian lipins for topics not covered here (3Csaki L.S. Dwyer J.R. Fong L.G. Tontonoz P. Young S.G. Reue K. Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling.Prog. Lipid Res. 2013; 52: 305-316Crossref PubMed Scopus (93) Google Scholar, 4Harris T.E. Finck B.N. Dual function lipin proteins and glycerolipid metabolism.Trends Endocrinol. Metab. 2011; 22: 226-233Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 5Bi L. Jiang Z. Zhou J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver.Alcohol Alcohol. 2015; 50: 146-151Crossref PubMed Scopus (25) Google Scholar, 6Zhang P. Reue K. Lipin proteins and glycerolipid metabolism: roles at the ER membrane and beyond.Biochim. Biophys. Acta Biomembr. 2017; 1859: 1583-1595Crossref PubMed Scopus (68) Google Scholar). In most mammalian tissues, TAG is synthesized by the glycerol 3-phosphate pathway through the sequential action of acyltransferases and lipin phosphatidic acid phosphatases (PAPs) (1Wang H. Airola M.V. Reue K. How lipid droplets “TAG” along: glycerolipid synthetic enzymes and lipid storage.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017; 1862: 1131-1145Crossref PubMed Scopus (62) Google Scholar, 2Coleman R.A. Mashek D.G. Mammalian triacylglycerol metabolism: synthesis, lipolysis, and signaling.Chem. Rev. 2011; 111: 6359-6386Crossref PubMed Scopus (170) Google Scholar) (Fig. 1). An alternative pathway for TAG synthesis is active primarily in the small intestine. This pathway utilizes monoacylglycerol (MAG), an abundant product of fat digestion, as the substrate for TAG synthesis (7Pan X. Hussain M.M. Gut triglyceride production.Biochim. Biophys. Acta. 2012; 1821: 727-735Crossref PubMed Scopus (71) Google Scholar, 8Yen C.L. Nelson D.W. Yen M.I. Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism.J. Lipid Res. 2015; 56: 489-501Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) (Fig. 1). As a component of the glycerol 3-phosphate pathway, lipin enzymes convert phosphatidic acid (PA) to diacylglycerol (DAG), which is a precursor of TAG as well as zwitterionic phospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine) (Fig. 1). Unlike acyltransferases, lipins do not have transmembrane domains and, instead, move freely from the cytosol to membranes containing PA, such as the ER, mitochondria, and autophagosomes/lysosomes (6Zhang P. Reue K. Lipin proteins and glycerolipid metabolism: roles at the ER membrane and beyond.Biochim. Biophys. Acta Biomembr. 2017; 1859: 1583-1595Crossref PubMed Scopus (68) Google Scholar). PAP activity was identified more than 60 years ago (9Smith S.W. Weiss S.B. Kennedy E.P. The enzymatic dephosphorylation of phosphatidic acids.J. Biol. Chem. 1957; 228: 915-922Abstract Full Text PDF PubMed Google Scholar), but due to properties of the PAP enzymes, biochemical purification eluded investigators for decades. The isolation of the lipin genes was accomplished through positional cloning of a mouse mutation that impacted TAG synthesis in adipose tissue, leading to the identification of a novel gene family that is evolutionarily conserved from humans to yeast (10Péterfy 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 (468) Google Scholar). Carman and colleagues purified yeast PA phosphohydrolase activity and discovered that its sequence matched the yeast ortholog of mammalian lipins, with the DxDxT motif located in a conserved protein domain that is required for enzymatic activity (11Han 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 (422) Google Scholar). Finck et al. (12Finck B.N. Gropler M.C. Chen Z. Leone T.C. Croce M.A. Harris T.E. Lawrence J.C. Kelly D.P. Lipin 1 is an inducible amplifier of the hepatic PGC-1α/PPARα regulatory pathway.Cell Metab. 2006; 4: 199-210Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar) demonstrated that lipin 1 also interacts with DNA-bound transcription factors through an LxxIL motif to coactivate transcription. These interactions include lipin 1 coactivation of PPARγ coactivator 1α and hepatocyte nuclear factor 4α in hepatocytes to regulate fatty acid oxidation, and corepression of nuclear factor of activated T cells c4 to regulate inflammatory gene expression in adipocytes (13Chen 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 (69) Google Scholar, 14Chen Z. Gropler M.C. Mitra M.S. Finck B.N. Complex interplay between the lipin 1 and the hepatocyte nuclear factor 4 α (HNF4α) pathways to regulate liver lipid metabolism.PLoS One. 2012; 7: e51320Crossref PubMed Scopus (31) Google Scholar, 15Kim H.B. Kumar A. Wang L. Liu G.H. Keller S.R. Lawrence J.C. Finck B.N. Harris T.E. Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors.Mol. Cell. Biol. 2010; 30: 3126-3139Crossref PubMed Scopus (82) Google Scholar). The three mammalian lipin proteins each have PAP activity, although with somewhat differing specific activities (Vmax lipin 1 >> lipin 2 > lipin 3), and exhibit distinct tissue distributions (3Csaki L.S. Dwyer J.R. Fong L.G. Tontonoz P. Young S.G. Reue K. Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling.Prog. Lipid Res. 2013; 52: 305-316Crossref PubMed Scopus (93) Google Scholar, 16Donkor 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 (292) Google Scholar). Lipin 1 is the exclusive lipin in human and mouse skeletal muscle and is also prominently expressed in adipose tissue, peripheral nerve, and testis, and at lower levels in liver, small intestine, and many other tissues. Lipin 2 is the most abundant lipin in liver, and also has substantial expression in small intestine, macrophages, and specific brain regions. The lipin 3 expression pattern overlaps that of lipin 1 and lipin 2, with highest levels in small intestine, adipose tissue, and liver. These expression patterns raise the possibility of cooperation among lipin proteins within cells and/or redundancy of lipin function in some cell types. The pathologies of genetic lipin deficiencies in human and mouse are consistent with their tissue distributions. Mutations in human LPIN1 (encoding lipin 1) cause episodic childhood rhabdomyolysis, which can be fatal (17Zeharia A. Shaag A. Houtkooper R.H. Hindi T. de Lonlay P. Erez G. Hubert L. Saada A. de Keyzer Y. Eshel G. et al.Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.Am. J. Hum. Genet. 2008; 83: 489-494Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 18Michot C. Hubert L. Brivet M. De Meirleir L. Valayannopoulos V. Müller-Felber W. Venkateswaran R. Ogier H. Desguerre I. Altuzarra C. et al.LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.Hum. Mutat. 2010; 31: E1564-E1573Crossref PubMed Scopus (97) Google Scholar, 19Michot C. Hubert L. Romero N.B. Gouda A. Mamoune A. Mathew S. Kirk E. Viollet L. Rahman S. Bekri S. et al.Study of LPIN1, LPIN2 LPIN3 in rhabdomyolysis and exercise-induced myalgia.J. Inherit. Metab. Dis. 2012; 35: 1119-1128Crossref PubMed Scopus (64) Google Scholar, 20Bergounioux J. Brassier A. Rambaud C. Bustarret O. Michot C. Hubert L. Arnoux J.B. Laquerriere A. Bekri S. Galene-Gromez S. et al.Fatal rhabdomyolysis in 2 children with LPIN1 mutations.J. Pediatr. 2012; 160: 1052-1054Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 21Schweitzer G.G. Collier S.L. Chen Z. Eaton J.M. Connolly A.M. Bucelli R.C. Pestronk A. Harris T.E. Finck B.N. Rhabdomyolysis-associated mutations in human LPIN1 lead to loss of phosphatidic acid phosphohydrolase activity.JIMD Rep. 2015; 23: 113-122Crossref PubMed Scopus (26) Google Scholar). Lipin 1-deficient mice develop muscle pathology when they are metabolically stressed (22Zhang P. Verity M.A. Reue K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.Cell Metab. 2014; 20: 267-279Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar), and also exhibit lipodystrophy (10Péterfy 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 (468) Google Scholar). The lipodystrophy phenotype led to the delineation of an important role for lipin PAP activity in adipocyte differentiation and TAG synthesis (23Phan J. Péterfy M. Reue K. Lipin expression preceding peroxisome proliferator-activated receptor-γ is critical for adipogenesis in vivo and in vitro.J. Biol. Chem. 2004; 279: 29558-29564Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 24Phan J. Reue K. Lipin, a lipodystrophy and obesity gene.Cell Metab. 2005; 1: 73-83Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar). A mouse model in which mature adipocytes express a Lpin1 allele that lacks PAP activity but retains coactivator function exhibits reduced adipose tissue TAG synthesis and lipolysis, which indicates a requirement for PAP activity in these functions (25Mitra M.S. Chen Z. Ren H. Harris T.E. Chambers K.T. Hall A.M. Nadra K. Klein S. Chrast R. Su X. et al.Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation.Proc. Natl. Acad. Sci. USA. 2013; 110: 642-647Crossref PubMed Scopus (46) Google Scholar). Interestingly, human lipin 1 deficiency is not characterized by lipodystrophy, and it appears that human lipin 1-deficient adipocytes exhibit compensatory mechanisms that are not present in mice, including lipin-independent TAG synthesis and reduced lipolysis of stored TAG (26Temprano A. Sembongi H. Han G-S. Sebastián D. Capellades J. Moreno C. Guardiola J. Wabitsch M. Richart C. Yanes O. et al.Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes.Diabetologia. 2016; 59: 1985-1994Crossref PubMed Scopus (22) Google Scholar). Mutations affecting human lipin 2 cause Majeed syndrome, a rare autoinflammatory disorder mainly encountered in Middle Eastern countries (27Ferguson P.J. Chen S. Tayeh M.K. Ochoa L. Leal S.M. Pelet A. Munnich A. Lyonnet S. Majeed H.A. El-Shanti H. 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: 551-557Crossref PubMed Scopus (309) Google Scholar, 28Al-Mosawi Z.S. Al-Saad K.K. Ijadi-Maghsoodi R. El-Shanti H.I. Ferguson P.J. A splice site mutation confirms the role of LPIN2 in Majeed syndrome.Arthritis Rheum. 2007; 56: 960-964Crossref PubMed Scopus (93) Google Scholar, 29Herlin T. Fiirgaard B. Bjerre M. Kerndrup G. Hasle H. Bing X. Ferguson P.J. Efficacy of anti-IL-1 treatment in Majeed syndrome.Ann. Rheum. Dis. 2013; 72: 410-413Crossref PubMed Scopus (130) Google Scholar). Lipin 2 mutations that inactivate PAP activity while leaving coactivator function intact are sufficient to cause Majeed syndrome (30Donkor J. Zhang P. Wong S. O'Loughlin L. Dewald J. Kok B.P.C. Brindley D.N. Reue K. A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2.J. Biol. Chem. 2009; 284: 29968-29978Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The disease manifests as mild dyserythropoietic anemia and episodic osteomyelitis, likely related to enhanced inflammasome activation in macrophages (discussed in a later section) (27Ferguson P.J. Chen S. Tayeh M.K. Ochoa L. Leal S.M. Pelet A. Munnich A. Lyonnet S. Majeed H.A. El-Shanti H. 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: 551-557Crossref PubMed Scopus (309) Google Scholar, 29Herlin T. Fiirgaard B. Bjerre M. Kerndrup G. Hasle H. Bing X. Ferguson P.J. Efficacy of anti-IL-1 treatment in Majeed syndrome.Ann. Rheum. Dis. 2013; 72: 410-413Crossref PubMed Scopus (130) Google Scholar, 31Lordén G. Sanjuán-García I. de Pablo N. Meana C. Alvarez-Miguel I. Pérez-García M.T. Pelegrín P. Balsinde J. Balboa M.A. Lipin-2 regulates NLRP3 inflammasome by affecting P2X 7 receptor activation.J. Exp. Med. 2017; 214: 511-528Crossref PubMed Scopus (66) Google Scholar). Lipin 2-deficient mice recapitulate mild anemia and have reduced trabecular bone density, but do not exhibit autoinflammation, likely due to absence of a trigger for these symptoms in mice housed in pathogen-free and environmentally controlled laboratory conditions (32Dwyer J.R. Donkor J. Zhang P. Csaki L.S. Vergnes L. Lee J.M. Dewald J. Brindley D.N. Atti E. Tetradis S. et al.Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum.Proc. Natl. Acad. Sci. USA. 2012; 109: E2486-E2495Crossref PubMed Scopus (61) Google Scholar). Compound deficiency for lipin 1 and lipin 2 causes embryonic lethality in the mouse (32Dwyer J.R. Donkor J. Zhang P. Csaki L.S. Vergnes L. Lee J.M. Dewald J. Brindley D.N. Atti E. Tetradis S. et al.Mouse lipin-1 and lipin-2 cooperate to maintain glycerolipid homeostasis in liver and aging cerebellum.Proc. Natl. Acad. Sci. USA. 2012; 109: E2486-E2495Crossref PubMed Scopus (61) Google Scholar). Human LPIN3 loss-of-function mutations have not been identified, and lipin 3-deficient mice do not have a major metabolic phenotype (33Csaki L.S. Dwyer J.R. Li X. Nguyen M.H.K. Dewald J. Brindley D.N. Lusis A.J. Yoshinaga Y. de Jong P. Fong L. et al.Lipin-1 and lipin-3 together determine adiposity in vivo.Mol. Metab. 2013; 3: 145-154Crossref PubMed Scopus (40) Google Scholar). This suggests that loss of lipin 3 can be compensated by the other two family members. Studies of mice that are deficient in lipin 3 in combination with either lipin 1 or lipin 2 have revealed collaborations among the lipin proteins in various tissues. Lipin 3 has a role alongside lipin 1 in adipocyte differentiation and adipose TAG storage, such that lipin 1/lipin3-deficient mice exhibit lipodystrophy that is even more profound than that in lipin 1-deficient mice (33Csaki L.S. Dwyer J.R. Li X. Nguyen M.H.K. Dewald J. Brindley D.N. Lusis A.J. Yoshinaga Y. de Jong P. Fong L. et al.Lipin-1 and lipin-3 together determine adiposity in vivo.Mol. Metab. 2013; 3: 145-154Crossref PubMed Scopus (40) Google Scholar). Mice with compound lipin 2/lipin 3 deficiency have impaired intestinal lipid homeostasis (discussed in a later section). As described above, lipin 1 mutations cause severe muscle dysfunction and destruction, and this has been shown to be associated with impaired PAP activity (21Schweitzer G.G. Collier S.L. Chen Z. Eaton J.M. Connolly A.M. Bucelli R.C. Pestronk A. Harris T.E. Finck B.N. Rhabdomyolysis-associated mutations in human LPIN1 lead to loss of phosphatidic acid phosphohydrolase activity.JIMD Rep. 2015; 23: 113-122Crossref PubMed Scopus (26) Google Scholar). Analysis of muscle ultrastructure in global or muscle-specific lipin 1-mutant mice revealed an accumulation of PA, dysfunctional mitochondria, and autophagosome accumulation, suggesting a defect in autophagy-mediated clearance of organelles (22Zhang P. Verity M.A. Reue K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.Cell Metab. 2014; 20: 267-279Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 34Schweitzer G.G. Collier S.L. Chen Z. McCommis K.S. Pittman S.K. Yoshino J. Matkovich S.J. Hsu F.F. Chrast R. Eaton J.M. et al.Loss of lipin 1-mediated phosphatidic acid phosphohydrolase activity in muscle leads to skeletal myopathy in mice.FASEB J. 2019; 33: 652-667Crossref PubMed Scopus (16) Google Scholar). Lipin 1 PAP activity (but not coactivator function) was required for the generation of mature autolysosomes that are responsible for the degradation of damaged organelles and proteins (22Zhang P. Verity M.A. Reue K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.Cell Metab. 2014; 20: 267-279Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Lipin 1 PAP activity generates DAG at the surface of autophagosomes/lysosomes, which activates a protein kinase D cascade that promotes fusion of autophagosomes with lysosomes to form functional autolysosomes (22Zhang P. Verity M.A. Reue K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.Cell Metab. 2014; 20: 267-279Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) (see Graphical Abstract). Interestingly, statin drugs attenuate protein kinase D activity, such that the combination of lipin 1 haploinsufficiency and statin drug therapy impairs autophagic flux and leads to myopathy (17Zeharia A. Shaag A. Houtkooper R.H. Hindi T. de Lonlay P. Erez G. Hubert L. Saada A. de Keyzer Y. Eshel G. et al.Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.Am. J. Hum. Genet. 2008; 83: 489-494Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 22Zhang P. Verity M.A. Reue K. Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.Cell Metab. 2014; 20: 267-279Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Thus, heterozygous LPIN1 mutations may be a risk factor for statin-related myopathy. As described above, human lipin 2 deficiency causes the autoinflammatory disease, Majeed syndrome. The symptoms of this disorder are attenuated by drugs that block the cytokine interleukin (IL)-1β or the IL-1β receptor (29Herlin T. Fiirgaard B. Bjerre M. Kerndrup G. Hasle H. Bing X. Ferguson P.J. Efficacy of anti-IL-1 treatment in Majeed syndrome.Ann. Rheum. Dis. 2013; 72: 410-413Crossref PubMed Scopus (130) Google Scholar). This clue led Balboa and colleagues to identify a role for lipin 2 in the priming and activation of the NLRP3 inflammasome, a multi-protein complex that assembles in macrophages in response to pathogen exposure and leads to the secretion of IL-1β and IL-18 (31Lordén G. Sanjuán-García I. de Pablo N. Meana C. Alvarez-Miguel I. Pérez-García M.T. Pelegrín P. Balsinde J. Balboa M.A. Lipin-2 regulates NLRP3 inflammasome by affecting P2X 7 receptor activation.J. Exp. Med. 2017; 214: 511-528Crossref PubMed Scopus (66) Google Scholar). NLRP3 priming in macrophages occurs in response to the activation of cell surface receptors (such as toll-like receptors) by pathogens or danger signals. Lipin 2 appears to limit the priming by affecting kinase signaling cascades and subsequent mRNA transcription of NLRP3 and IL-1β (31Lordén G. Sanjuán-García I. de Pablo N. Meana C. Alvarez-Miguel I. Pérez-García M.T. Pelegrín P. Balsinde J. Balboa M.A. Lipin-2 regulates NLRP3 inflammasome by affecting P2X 7 receptor activation.J. Exp. Med. 2017; 214: 511-528Crossref PubMed Scopus (66) Google Scholar) (Graphical Abstract). Lipin 2 also influences the activation of the NLRP3 inflammasomes by maintaining cellular membrane cholesterol levels, which influence signaling through purinergic receptors, leading to inflammasome assembly and caspase-1 production. Caspase-1 processes the IL-1β pro-peptide to its mature active form, which is enhanced in Majeed syndrome. The role of lipin 2 in inflammasome activation is similar in macrophages isolated from mice and humans (31Lordén G. Sanjuán-García I. de Pablo N. Meana C. Alvarez-Miguel I. Pérez-García M.T. Pelegrín P. Balsinde J. Balboa M.A. Lipin-2 regulates NLRP3 inflammasome by affecting P2X 7 receptor activation.J. Exp. Med. 2017; 214: 511-528Crossref PubMed Scopus (66) Google Scholar), suggesting that the muted inflammatory phenotype in lipin 2-deficient mice compared with humans may reflect the pathogen-free conditions that laboratory mice are raised in rather than a physiological difference between species. The role of lipin 2 in innate immune function also likely underlies the observed association of lipin 2 missense mutations with psoriasis, and suggests that lipin 2 activity should be considered in the evaluation of autoinflammatory conditions of unknown etiology (35Milhavet F. Cuisset L. Hoffman H.M. Slim R. El-Shanti H. Aksentijevich I. Lesage S. Waterham H. Wise C. Sarrauste de Menthiere C. et al.The infevers autoinflammatory mutation online registry: update with new genes and functions.Hum. Mutat. 2008; 29: 803-808Crossref PubMed Scopus (201) Google Scholar). Macrophages also express lipin 1. Recent studies suggest that lipin 1 may amplify inflammation by promoting macrophage production of the proinflammatory cytokine, IL-23, in response to toll-like receptor 4 activation (36Meana C. Peña L. Lordén G. Esquinas E. Guijas C. Valdearcos M. Balsinde J. Balboa M.A. Lipin-1 integrates lipid synthesis with proinflammatory responses during TLR activation in macrophages.J. Immunol. 2014; 193: 4614-4622Crossref PubMed Scopus (37) Google Scholar). Lipin 1-deficient mice have reduced gut inflammation in experimentally induced colon cancer, which is associated with reduced infiltration of macrophages into colon tumors and reduced macrophage activation and PAP activity (37Meana C. García-Rostán G. Peña L. Lordén G. Cubero Á. Orduña A. Győrffy B. Balsinde J. Balboa M.A. The phosphatidic acid phosphatase lipin-1 facilitates inflammation-driven colon carcinogenesis.JCI Insight. 2018; 3: 97506Crossref PubMed Scopus (24) Google Scholar). Additionally, LPIN1 expression levels have prognostic value in the clinical course for some subtypes of colon cancer. Lipin 2 and lipin 3 are expressed in a wide array of tissues, but in most cases, lipin 1 is also present and appears to be the dominant player owing to its higher PAP-specific activity. An exception is the small intestine, which expresses lipin 2 and lipin 3 without lipin 1 (16Donkor 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 (292) Google Scholar). The small intestine absorbs ∼95% of dietary TAGs, which are hydrolyzed to MAGs and free fatty acids in the intestinal lumen (7Pan X. Hussain M.M. Gut triglyceride production.Biochim. Biophys. Acta. 2012; 1821: 727-735Crossref PubMed Scopus (71) Google Scholar, 8Yen C.L. Nelson D.W. Yen M.I. Intestinal triacylglycerol synthesis in fat absorption and systemic energy metabolism.J. Lipid Res. 2015; 56: 489-501Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In enterocytes, these components are reassembled into TAGs, which may be transiently stored as lipid droplets or incorporated into chylomicron particles and secreted into the circulation through lymphatic ducts. It is estimated that 70–80% of intestinal TAG synthesis for chylomicron production is via the MAG acyltransferase (MGAT) pathway, and genetic ablation of Mogat2 (encoding mouse intestinal MGAT2) delays the rate of triglyceride appearance in the circulation after a meal (38Yen C-L.E. Cheong M-L. Grueter C. Zhou P. Moriwaki J. Wong J.S. Hubbard B. Marmor S. Farese R.V. Deficiency of the intestinal enzyme acyl CoA:monoacylglycerol acyltransferase-2 protects mice from metabolic disorders induced by high-fat feeding.Nat. Med. 2009; 15: 442-446Crossref PubMed Scopus (133) Google Scholar). This raises a question of whether the enzymes of the glycerol 3-phosphate pathway serve a unique function in intestinal lipid metabolism or are a redundant mechanism for TAG synthesis. We used mouse models to investigate the role of lipins 2 and 3 in small intestinal lipid metabolism (39Zhang P. Csaki L.S. Ronquillo E. Baufeld L.J. Lin J.Y. Gutierrez A. Dwyer J.R. Brindley D.N. Fong L.G. Tontonoz P. et al.Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis.J. Clin. Invest. 2019; 129: 281-295Crossref PubMed Scopus (21) Google Scholar). The lack of either lipin 2 or lipin 3 alone leads to a reduction in intestinal PAP activity, but has little effect on intestinal lipid homeostasis. However, deletion of both lipin 2 and lipin 3 leads to 25% reduced body weight on a chow diet and lethality on a high-fat diet within a few days. Lipin 2/3-deficient enterocytes incorporate dietary fatty acids into TAGs (presumably through the MGAT pathway), but tend to store the resulting TAGs in cytosolic lipid droplets rather than incorporate them into nascent chylomicron particles in the ER lumen. Lipin 2/3 PAP activity (but not coactivator activity) regulates enterocyte phospholipid levels and membrane composition, which influences the availability of TAGs in the ER lumen to associate with the key chylomicron protein (apolipoprotein B48). Lipin PAP activity may influence enterocyte phospholipid levels in at least two ways: 1) by converting PA to DAG, a precursor of phosphatidylcholine; and 2) by modulating PA levels, which indirectly regulate the levels of the key phosphatidylcholine biosynthetic enzyme [CTP:phosphocholine cytidylyltransferase α (CCTα)] (39Zhang P. Csaki L.S. Ronquillo E. Baufeld L.J. Lin J.Y. Gutierrez A. Dwyer J.R. Brindley D.N. Fong L.G. Tontonoz P. et al.Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis.J. Clin. Invest. 2019; 129: 281-295Crossref PubMed Scopus (21) Google Scholar) (Graphical Abstract). Chylomicron assembly in lipin 2/3-deficient enterocytes can be rescued by inhibiting CCTα activity to normalize cellular phospholipid levels. Thus, lipin 2/3 PAP activity in enterocytes hydrolyzes PA, regulates phospholipid synthesis, and promotes conditions that allow TAG transport into the ER lumen for chylomicron assembly. The involvement of lipins in important physiological processes has led to interest in understanding how lipin activity is regulated. Prior to the identification of the genes encoding lipins, it was known that PAP activity is regulated by fasting, glucocorticoids, and alcohol [reviewed in (1Wang H. Airola M.V. Reue K. How lipid droplets “TAG” along: glycerolipid synthetic enzymes and lipid storage.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017; 1862: 1131-1145Crossref PubMed Scopus (62) Google Scholar, 4Harris T.E. Finck B.N. Dual function lipin proteins and glycerolipid metabolism.Trends Endocrinol. Metab. 2011; 22: 226-233Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 5Bi L. Jiang Z. Zhou J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver.Alcohol Alcohol. 2015; 50: 146-151Crossref PubMed Scopus (25) Google Scholar)]. We now know that the lipin genes are regulated by the glucocorticoid receptor, the sterol response element-binding protein 1, estrogen-related receptor α/γ, hepatocyte nuclear factor 4α, nuclear respiratory factor 1, and PPARγ coactivator 1α [reviewed in (1Wang H. Airola M.V. Reue K. How lipid droplets “TAG” along: glycerolipid synthetic enzymes and lipid storage.Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017; 1862: 1131-1145Crossref PubMed Scopus (62) Google Scholar, 4Harris T.E. Finck B.N. Dual function lipin proteins and glycerolipid metabolism.Trends Endocrinol. Metab. 2011; 22: 226-233Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 5Bi L. Jiang Z. Zhou J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver.Alcohol Alcohol. 2015; 50: 146-151Crossref PubMed Scopus (25) Google Scholar)]. Lpin1 expression is also regulated through the action of microRNAs, which may fine-tune lipin 1 expression levels in response to stimuli such as alcohol and lipopolysaccharide (5Bi L. Jiang Z. Zhou J. The role of lipin-1 in the pathogenesis of alcoholic fatty liver.Alcohol Alcohol. 2015; 50: 146-151Crossref PubMed Scopus (25) Google Scholar). A key determinant of lipin PAP activity is posttranslational modification of lipin proteins. In mammalian lipins, posttranslational modifications include phosphorylation, sumoylation, acetylation, and ubiquitination (40Harris T.E. Huffman T.A. Chi A. Shabanowitz J. Hunt D.F. Kumar A. Lawrence 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 (169) Google Scholar, 41Eaton J.M. Mullins G.R. Brindley D.N. Harris T.E. Phosphorylation of lipin 1 and charge on the phosphatidic acid head group control its phosphatidic acid phosphatase activity and membrane association.J. Biol. Chem. 2013; 288: 9933-9945Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 42Eaton J.M. Takkellapati S. Lawrence R.T. McQueeney K.E. Boroda S. Mullins G.R. Sherwood S.G. Finck B.N. Villen J. Harris T.E. Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation.J. Biol. Chem. 2014; 289: 18055-18066Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 43Peterson T.R. Sengupta S.S. Harris T.E. Carmack A.E. Kang S.A. Balderas E. Guertin D.A. Madden K.L. Carpenter A.E. Finck B.N. et al.mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.Cell. 2011; 146: 408-420Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar, 44Liu G-H. Gerace L. Sumoylation regulates nuclear localization of lipin-1α in neuronal cells.PLoS One. 2009; 4: e7031Crossref PubMed Scopus (62) Google Scholar, 45Péterfy M. Harris T.E. Fujita N. Reue K. Insulin-stimulated interaction with 14-3-3 promotes cytoplasmic localization of lipin-1 in adipocytes.J. Biol. Chem. 2010; 285: 3857-3864Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 46Han S. Bahmanyar S. Zhang P. Grishin N. Oegema K. Crooke R. Graham M. Reue K. Dixon J.E. Goodman J.M. Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway.J. Biol. Chem. 2012; 287: 3123-3137Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 47Li T.Y. Song L. Sun Y. Li J. Yi C. Lam S.M. Xu D. Zhou L. Li X. Yang Y. et al.Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate.Nat. Commun. 2018; 9: 1916Crossref PubMed Scopus (30) Google Scholar, 48Shimizu K. Fukushima H. Ogura K. Lien E.C. Nihira N.T. Zhang J. North B.J. Guo A. Nagashima K. Nakagawa T. et al.The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.Sci. Signal. 2017; 10: eaah4117Crossref PubMed Scopus (33) Google Scholar) (Fig. 2). Modifications that promote lipin 1 translocation to the ER membrane (and membranes of other organelles) regulate PAP activity by allowing lipin protein access to its substrate, PA [reviewed in (6Zhang P. Reue K. Lipin proteins and glycerolipid metabolism: roles at the ER membrane and beyond.Biochim. Biophys. Acta Biomembr. 2017; 1859: 1583-1595Crossref PubMed Scopus (68) Google Scholar)]. Harris and colleagues have identified differences between lipin 1 and the other two lipin family members in posttranslational modification and subcellular localization (42Eaton J.M. Takkellapati S. Lawrence R.T. McQueeney K.E. Boroda S. Mullins G.R. Sherwood S.G. Finck B.N. Villen J. Harris T.E. Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation.J. Biol. Chem. 2014; 289: 18055-18066Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 49Boroda S. Takkellapati S. Lawrence R.T. Entwisle S.W. Pearson J.M. Granade M.E. Mullins G.R. Eaton J.M. Villén J. Harris T.E. The phosphatidic acid–binding, polybasic domain is responsible for the differences in the phosphoregulation of lipins 1 and 3.J. Biol. Chem. 2017; 292: 20481-20493Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). While all three lipins are phosphorylated at multiple sites, only lipin 1 phosphorylation is regulated by insulin and mammalian target of rapamycin. Furthermore, whereas lipin 1 phosphorylation influences its membrane association, lipin 2 phosphorylation does not, and sequence differences in a polybasic domain underlie differences in phosphoregulation between lipin 1 and lipin 3. Understanding the properties of biochemical regulation of the three lipin family members may shed additional light on their individual physiological roles. In the years since molecular cloning of the lipin genes, we have learned that Mendelian mutations in two of the lipins cause severe diseases, and have delineated critical and unforeseen roles for lipin PAP regulation of lipid intermediates in protein and organelle quality control by autophagy, regulation of NLRP3 inflammasome activation, and lipoprotein assembly. Much remains to be discovered. One key area for future attention is the determination of lipin protein structure, which will shed additional light on lipin PAP and transcriptional activities. Another area that deserves attention is the further elucidation of the biochemical and physiological division of labor between the three lipin proteins. Finally, questions arise as to whether lipin proteins are viable therapeutic targets to modulate TAG accumulation in conditions such as obesity or fatty liver. Major challenges exist on this front. As illustrated by genetic lipin deficiencies, inhibition of lipin activity may be beneficial in some tissues but detrimental in others. Furthermore, because the dual activities of lipin proteins as PAP enzymes and transcriptional cofactors may oppose one another (i.e., PAP modulation of TAG synthesis vs. transcriptional activation of fatty acid oxidation), a global inhibition of lipin function will likely not be useful. Compounds that influence lipin protein subcellular localization may be a more promising approach, but further understanding of the regulation of lipin localization and activities is required. CTP:phosphocholine cytidylyltransferase α diacylglycerol interleukin monoacylglycerol monoacylglycerol acyltransferase phosphatidic acid phosphatidic acid phosphatase triacylglycerol
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