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FLASH GENE
Symbol LPIN1 contributors: mct - updated : 12-06-2016
HGNC name lipin 1
HGNC id 13345
EXPRESSION
Type
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Cardiovascularheart   highly Homo sapiens
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Connectiveadipose  highly Homo sapiens
Muscularstriatumskeletal highly
Muscularstriatumcardiacmyocardiumhighly Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
not specificadipocyte Homo sapiens
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal domain important for its catalytic activity, nuclear localization, and binding to PPP1CC
  • N-LIP interacting with several nuclear proteins, and C-LIP domains exhibit conservation between family members
  • both the N- and C-terminal regions of lipin 1 mediate its oligomerization in a head-to-head/tail-to-tail manner
  • P, serine AA 106, which is known to be phosphorylated in response to insulin
  • a NLS, nuclear localization signal
  • a TAD (transcriptional activation domain), between residues 217 and 399, which is critical for the activation of PPARG, but not PPARA
  • a coil-loop structure for the insulin-dependent phosphorylation site
  • DXDXT, PAP1 enzyme active site
  • LXXIL, transcription factor interaction domain
  • catalytic domain LNS2 (Lipin/Ned1/Smp2) at AAs 674830
  • a polybasic motif having a role as both a lipid binding motif and a primary nuclear localization sequence, and necessary for full expression of the biological activity of the protein in intracellular lipid metabolism and transcriptional control of adipogenesis
  • mono polymer homomer , octamer
    HOMOLOGY
    interspecies ortholog to murine Lpin1
    homolog to rattus Rn.8183
    homolog to Drosophila CG8709
    homolog to C.elegans H37A05.1
    intraspecies homolog to LPIN2
    homolog to LPIN3
    Homologene
    FAMILY
  • lipin family
  • Mg2+-dependent phosphatidate phoshatases (PAP1 enzymes)family
  • conserved haloacid dehalogenase superfamily
  • CATEGORY
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,outer
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    text
  • localized to the cytosol, endoplasmic reticulum, and nucleus
  • lipid phosphatase enzymes at the endoplasmic reticular membrane, that can rapidly translocate within the cell
  • hyperphosphorylated LPIN1 remains sequestered in the cytosol, whereas hypophosphorylated LPIN1 translocates to the endoplasmic reticulum and nucleus
  • basic FUNCTION
  • playing a role in normal adipose tissue development and in triglyceride metabolism
  • its expression in differentiating preadipocytes is required for normal expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma and CCAAT enhancer binding protein alpha, and for the synthesis of triacylglycerol
  • required for adipocyte differentiation and in the maintenance of adipocyte function
  • required prior to PPARgamma during adipocyte differentiation
  • playing a role in the regulation of the glucose and insulin levels
  • influences lipid metabolism and glucose homeostasis in diverse tissues including adipose tissue, skeletal muscle, and liver
  • in addition to its role in glycerolipid synthesis, also operates as a transcriptional coactivator, working in collaboration with known nuclear receptors and coactivators to modulate lipid metabolism gene expression
  • having a distinct and non-redundant function in regulating lipid production during the cell cycle and adipocyte differentiation
  • act as a transcriptional coactivator in liver, directly interacting with nuclear receptors such as PPARA and the coactivator PGC1A
  • might be involved in exercise-induced mitochondrial biogenesis in skeletal muscle
  • has transcriptional coactivator activity in hepatocytes
  • plays a dual role, in the cytoplasm, acting as a phosphatidate phosphatase 1 (PAP1) converting phosphatidic acid to diacylglycerol, and in the nucleus functions as a transcriptional co-activator through interaction with transcription factors including PPARA and PPARGC1A, which regulate the expression of genes encoding FAO and respiratory chain (RC) enzymes
  • muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis
  • functions as an amplifier of the network between PPARG and CEBPA, resulting in the maintenance of high levels of the specific gene expression that are required for adipogenesis and mature adipocyte functions
  • could be involved in the regulation of gene transcription by interacting with transcription factors
  • critical role of LIPIN1 in the perturbation of hepatic insulin signaling
  • possesses phosphatidate (PA) phosphatase (3-sn-phosphatidate phosphohydrolase activity
  • potentially important link between triacylglycerol synthesis and adipose tissue inflammation
  • also play crucial roles in the nucleus as transcriptional regulatory proteins
  • lipin 1, 2, and 3 are bifunctional intracellular proteins that regulate metabolism by acting as coregulators of DNA-bound transcription factors and also dephosphorylate phosphatidate to form diacylglycerol
  • principal lipin protein in the myocardium and is regulated in response to physiologic and pathologic stimuli that impact cardiac metabolism
  • promotes nuclear remodeling and mediates the effects of MTOR on SREBF target gene, SREBF promoter activity, and nuclear SREBF1 and SREBF2 protein abundance
  • as both necessary and sufficient for mediating the effects of MTOR inhibition on SREBF transcriptional activity
  • functions as a phosphatidate phosphatase (PAP) enzyme in the glycerol 3-phosphate pathway for triglyceride storage and as a transcriptional coactivator/corepressor for metabolic nuclear receptors
  • Lipin-1 modulation of phosphatidic acid levels is required for early steps in adipogenesis
  • is critical for lipid synthesis and homeostasis in adipose tissue, liver, muscle, and peripheral nerves
  • plays crucial roles in the regulation of lipid metabolism and cell differentiation in adipocytes
  • ER stress might be involved in the pathogenesis of obesity through lipin-1 depletion
  • is essential for increased capacity for beta-oxidation in fasted livers, and it is also a phosphatidate phosphatase involved in triacylglycerol and phospholipid synthesis
  • functions as a key regulator of PPARG activity through its ability to release co-repressors and recruit co-activators via a mechanism other than PPARA activation
  • lipin-1 phosphatidic acid phosphatase (PAP) activity is a component of the macroautophagy pathway
  • in addition to their roles during early adipogenesis, lipins also have a role in lipid droplet biogenesis
  • phosphatidate phosphatase in glycerolipid biosynthesis and signal transduction
  • also serves as a transcriptional co-regulator to control lipid metabolism and adipogenesis
  • LPIN2 functions likely as a constitutively active phosphatidic acid (PA) phosphatase in stark contrast to the high degree of phosphorylation-mediated regulation of LPIN1
  • Mg(2+)-dependent phosphatidic acid phosphatase involved in the de novo synthesis of phospholipids and triglycerides
  • unanticipated role as a mediator of macrophage proinflammatory activation and support a critical link between lipid biosynthesis and systemic inflammatory responses
  • CELLULAR PROCESS cell life, differentiation
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS
    text adipocyte differentiation
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
    triglyceride metabolism
    a component
  • lipin proteins function as oligomeric complexes and that the three mammalian lipin isoforms can form combinatorial units
  • key component of the MTOR-SREBF pathway
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • physically interacts with nuclear receptors such as PPARA and PGC1A
  • interacting with CTDNEP1 (Lipin cellular location, protein partners, and biological function are directed by phosphorylation-dephosphorylation events catalyzed by the phosphoserine phosphatase CTDNEP1)
  • functional interaction between lipin 1 and the nuclear factor of activated T cells c4 (NFATC4) (represses NFATC4 transcriptional activity through protein-protein interaction, and LPIN1 is present at the promoters of NFATC4 transcriptional targets)
  • binds to phosphatidic acid (PA) present on mitochondrial membranes to promote mitochondrial fission and influence mitochondrial size
  • its phosphatidic acid phosphatase activity, but not its coactivator activity, is required for induction of PPARG
  • NFE2L1 binds to the antioxidant response elements (AREs) in regulatory regions of the LPIN1 and PPARGC1B genes
  • LPIN1 enhances the tumour-promoting function of insulin receptor substrate 1 (IRS1) by controlling IRS1 stability
  • cell & other
  • associates with lipid droplets and regulates the activation of cytosolic group IVA phospholipase A(2)alpha in monocyte-derived macrophage
  • REGULATION
    activated by glucocorticoids
    inhibited by NFE2L1 deficiency leading to the reduced expression of the transcriptional coactivator genes LPIN1 and PPARGC1B
    Other dephosphorylated by CTDNEP1
    insulin may modulate the cellular function of lipin-1 by regulating its subcellular localization through interactions with 14-3-3 proteins
    modified by sumoylation at two consensus sumoylation sites (sumoylated at relatively high levels in brain, where lipin-1alpha is the predominant form)
    ASSOCIATED DISORDERS
    corresponding disease(s) MGAR
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    in lipodystrophy
    constitutional     --over  
    in liver, in response to fasting and glucocorticoids
    constitutional germinal mutation      
    cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy
    constitutional     --low  
    of total LPIN1 mRNA expression in subjects with obesity was found in visceral adipose tissue similarly to that in subcutaneous tissue
    Susceptibility
  • to obesity in males
  • to statin-induced myopathy
  • Variant & Polymorphism SNP , other
  • increasing the risk of obesity in males
  • polymorphisms increasing the risk of statin-induced myopathy
  • Candidate gene lipodysytropy syndromes
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    may be a promising drug target for anticancer therapy
    ANIMAL & CELL MODELS
  • natural Lpin1 mutant mouse strain fld displays a phenotype mainly characterized by transient postnatal fatty liver (before weaning) and persistent lipodystrophy
  • concurrent Lpin1 and Nrcam mouse mutations result in severe peripheral neuropathy with transitory hindlimb paralysis
  • hearts of mice lacking lipin 1 (fld mice) exhibit accumulation of phosphatidate
  • Lpin11Hubr rats developed hypomyelination and mild lipodystrophy
  • Lipin-1-deficient fld mice exhibit lipodystrophy characterized by dramatically reduced adipose tissue mass, absence of mature adipocytes, and metabolic dysregulation
  • loss of Lpin1 in mice inhibits adipogenesis at an early stage of differentiation and results in a lipodystrophic phenotype
  • lipin-1-related myopathy in the mouse is associated with a blockade in autophagic flux and accumulation of aberrant mitochondria