Abstract
The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is an inhibitor of the insulin receptor. Variants of ENPP1 are associated with infantile arterial calcification, obesity, and insulin resistance. To study the functional relevance of this protein in vivo, we cloned rabbit ENPP1 and studied its regulation in experimentally induced diabetes mellitus. We amplified and sequenced the complete coding sequence of rabbit ENPP1 gene out of a liver cDNA library using redundant primers deduced from other species. Next, we performed quantitative PCR of ENPP1 to study the tissue distribution of ENPP1 expression and its regulation in an alloxan-dependent diabetes model. The putative rabbit ENPP1 protein contains 873 amino acids and is highly conserved when compared with human ENPP1 (90% amino acid identity). Particularly high levels of ENPP1 mRNA expression were found in adipose tissue. Quantitative PCR analysis revealed a significant upregulation of ENPP1 transcription in liver (p = 0.025) and brain (p = 0.034) of diabetic rabbits compared with controls. Hepatic ENPP1 expression is induced in diabetic rabbits when compared with controls. This approximately twofold upregulation of ENPP1 mRNA in rabbit liver parallels previous findings in patients with type 2 diabetes mellitus. We provide further molecular information about ENPP1 as a potential pharmacologic target and characterize its regulation in an insulin-dependent diabetes mellitus animal model.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abate N, Chandalia M, Satija P, Adams-Huet B, Grundy SM, et al. (2005) ENPP1/PC-1 K121Q polymorphism and genetic susceptibility to type 2 diabetes. Diabetes 54, 1207–1213
Bacci S, Ludovico O, Prudente S, Zhang YY, Di Paola R, et al. (2005) The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction. Diabetes 54, 3021–3025
Buckley MF, Loveland KA, McKinstry WJ, Garson OM, Goding JW (1990) Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human molecule, amino acid sequence, and chromosomal location. J Biol Chem 265, 17506–17511
Canani LH, Ng DP, Smiles A, Rogus JJ, Warram JH, et al. (2002) Polymorphism in ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1/PC-1) and early development of advanced diabetic nephropathy in type 1 diabetes. Diabetes 51, 1188–1193
Dong H, Maddux BA, Altomonte J, Meseck M, Accili D, et al. (2005) Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes 54, 367–372
Elsner M, Tiedge M, Guldbakke B, Munday R, Lenzen S (2002) Importance of the GLUT2 glucose transporter for pancreatic beta cell toxicity of alloxan. Diabetologia 45, 1542–1549
Endler G, Mannhalter C, Sunder-Plassmann H, Schillinger M, Klimesch A, et al. (2002) The K121Q polymorphism in the plasma cell membrane glycoprotein 1 gene predisposes to early myocardial infarction. J Mol Med 80, 791–795
Gander R, Eller P, Kaser S, Theurl I, Walter D, et al. (2002) Molecular characterization of rabbit phospholipid transfer protein: choroid plexus and ependyma synthesize high levels of phospholipid transfer protein. J Lipid Res 43, 636–645
Maddux BA, Goldfine ID (2000) Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes 49, 13–19
Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, et al. (1995) Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 373, 448–451
Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Okazaki H, et al. (2004) Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice. Diabetes 53, 560–569
Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, et al. (2005) Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet 37, 863–867
Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, et al. (1998) Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet 19, 271–273
Pender C, Ortmeyer HK, Hansen BC, Goldfine ID, Youngren JF (2002) Elevated plasma cell membrane glycoprotein levels and diminished insulin receptor autophosphorylation in obese, insulin-resistant rhesus monkeys. Metabolism 51, 465–470
Rerup CC (1970) Drugs producing diabetes through damage of the insulin secreting cells. Pharmacol Rev 22, 485–518
Ritsch A, Tancevski I, Schgoer W, Pfeifhofer C, Gander R, et al. (2004) Molecular characterization of rabbit scavenger receptor class B types I and II: portal to central vein gradient of expression in the liver. J Lipid Res 45, 214–222
Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, et al. (2003) Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet 34, 379–381
Sakoda H, Ogihara T, Anai M, Funaki M, Inukai K, et al. (1999) No correlation of plasma cell 1 overexpression with insulin resistance in diabetic rats and 3T3-L1 adipocytes. Diabetes 48, 1365–1371
Youngren JF, Maddux BA, Sasson S, Sbraccia P, Tapscott EB, et al. (1996) Skeletal muscle content of membrane glycoprotein PC-1 in obesity. Relationship to muscle glucose transport. Diabetes 45, 1324–1328
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Eller, P., Hochegger, K., Wehinger, A. et al. Hepatic ENPP1 expression is induced in diabetic rabbits. Mamm Genome 17, 886–891 (2006). https://doi.org/10.1007/s00335-006-0028-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-006-0028-4