Apolipoprotein A-V Modulates Insulin Secretion in Pancreatic β-cells Through its Interaction with Midkine

Apolipoprotein A-V is an important determinant of plasma triglyceride level in both humans and mice. This study showed the physiological impact of apoA-V on insulin secretion in rat pancreatic β-cells (INS-1 cells). In order to precise the mechanism of action, binding experiments coupled to mass spectrometry were performed to identify a potential membrane receptor. Results showed an interaction between apoA-V and midkine protein. Confocal microscopy confirmed the plasma membrane co-localisation of this two-proteins after the treatment of INS-1 cells with the apo-AV recombinant protein and indicated that the cell surface midkine could be involved in apoA-V endocytosis, since these two proteins were co-translocated at the plasma membrane or in the cytosol compartment. This co-localisation is correlated with an increase in insulin secretion in a dose dependant manner during short incubation period. Reduction of midkine expression by small interfering RNA duplexes revealed a decrease in the ability of these transfected cells to secrete insulin in presence of apoA-V. Competition experiments for the apoA-V-midkine binding at the cell surface using antibody directed against midkine is able to influence INS-1 cell function as insulin secretion. Our results showed apoA-V ability to enhance insulin secretion in β-cells and provide evidence of an internalization pathway involving the midkine as partner.

[1]  C. Sergheraert,et al.  Glucose regulates LXRα subcellular localization and function in rat pancreatic β-cells , 2006, Cell Research.

[2]  J. Fruchart,et al.  Is apolipoprotein A5 a novel regulator of triglyceride‐rich lipoproteins? , 2006, Annals of medicine.

[3]  C. Sergheraert,et al.  Glucose regulates LXRalpha subcellular localization and function in rat pancreatic beta-cells. , 2006, Cell Research.

[4]  X. Prieur,et al.  Thyroid Hormone Regulates the Hypotriglyceridemic Gene APOA5* , 2005, Journal of Biological Chemistry.

[5]  L. Pennacchio,et al.  Transcriptional Regulation of Apolipoprotein A5 Gene Expression by the Nuclear Receptor RORα , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[6]  Y. Chiu,et al.  Impact of Apolipoprotein A5 Polymorphisms on Insulin Sensitivity and β-cell Function , 2005, Pancreas.

[7]  P. Strömstedt,et al.  Identification of the human ApoAV gene as a novel RORα target gene , 2005 .

[8]  L. Pennacchio,et al.  Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase. , 2005, The Journal of biological chemistry.

[9]  L. Pennacchio,et al.  Insulin-Mediated Down-Regulation of Apolipoprotein A5 Gene Expression through the Phosphatidylinositol 3-Kinase Pathway: Role of Upstream Stimulatory Factor , 2005, Molecular and Cellular Biology.

[10]  A. Boodhoo,et al.  The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. , 2005, Clinical chemistry.

[11]  A. Cantafora,et al.  Inherited Apolipoprotein A-V Deficiency in Severe Hypertriglyceridemia , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[12]  P. Strömstedt,et al.  Identification of the human ApoAV gene as a novel RORalpha target gene. , 2005, Biochemical and biophysical research communications.

[13]  L. Pennacchio,et al.  The Liver X Receptor Ligand T0901317 Down-regulates APOA5 Gene Expression through Activation of SREBP-1c* , 2004, Journal of Biological Chemistry.

[14]  L. Pennacchio,et al.  Transcriptional Regulation of Apolipoprotein A5 Gene Expression by theNuclear Receptor ROR alpha , 2004 .

[15]  K. V. van Dijk,et al.  ApoAV Reduces Plasma Triglycerides by Inhibiting Very Low Density Lipoprotein-Triglyceride (VLDL-TG) Production and Stimulating Lipoprotein Lipase-mediated VLDL-TG Hydrolysis* , 2004, Journal of Biological Chemistry.

[16]  L. Pennacchio,et al.  Analysis of Apolipoprotein A5, C3, and Plasma Triglyceride Concentrations in Genetically Engineered Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[17]  V. Lánská,et al.  The influence of APOAV polymorphisms (T‐1131>C and S19>W) on plasma triglyceride levels and risk of myocardial infarction , 2004, Clinical genetics.

[18]  Len A Pennacchio,et al.  Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5. , 2004, Biochemical and biophysical research communications.

[19]  X. Prieur,et al.  The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-α and Contains a Novel Farnesoid X-activated Receptor Response Element* , 2003, Journal of Biological Chemistry.

[20]  L. Pennacchio,et al.  Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor α Activators* , 2003, The Journal of Biological Chemistry.

[21]  B. Tomlinson,et al.  APOA5‐1131T>C polymorphism is associated with triglyceride levels in Chinese men , 2003, Clinical genetics.

[22]  P. Talmud,et al.  Contribution of APOA5 gene variants to plasma triglyceride determination and to the response to both fat and glucose tolerance challenges. , 2003, Biochimica et biophysica acta.

[23]  M. Olivier,et al.  Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. , 2002, Human molecular genetics.

[24]  Jonathan C. Cohen,et al.  Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. , 2002, Human molecular genetics.

[25]  M. Hirai,et al.  Nuclear Targeting by the Growth Factor Midkine , 2002, Molecular and Cellular Biology.

[26]  C. Powers,et al.  Midkine Binds to Anaplastic Lymphoma Kinase (ALK) and Acts as a Growth Factor for Different Cell Types* , 2002, The Journal of Biological Chemistry.

[27]  S. Tomura,et al.  Association found between the promoter region polymorphism in the apolipoprotein A-V gene and the serum triglyceride level in Japanese schoolchildren , 2002, Human Genetics.

[28]  J. Ribalta,et al.  Newly identified apolipoprotein AV gene predisposes to high plasma triglycerides in familial combined hyperlipidemia. , 2002, Clinical chemistry.

[29]  R. Chamuleau,et al.  Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. , 2002, Biochemical and biophysical research communications.

[30]  P. Wilson,et al.  Diabetes mellitus and coronary heart disease. , 2001, Endocrinology and metabolism clinics of North America.

[31]  P. Reitsma,et al.  Apolipoprotein A-V , 2001, The Journal of Biological Chemistry.

[32]  K. Zou,et al.  Midkine binds to 37-kDa laminin binding protein precursor, leading to nuclear transport of the complex. , 2001, Experimental cell research.

[33]  Jonathan C. Cohen,et al.  An Apolipoprotein Influencing Triglycerides in Humans and Mice Revealed by Comparative Sequencing , 2001, Science.

[34]  C. Locht,et al.  Subtilisin‐like autotransporter serves as maturation protease in a bacterial secretion pathway , 2001, The EMBO journal.

[35]  D. Jonas,et al.  New molecular mediators in tumor angiogenesis , 2000, Journal of cellular and molecular medicine.

[36]  K. Zou,et al.  LDL receptor-related protein as a component of the midkine receptor. , 2000, Biochemical and biophysical research communications.

[37]  Teven,et al.  MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION , 2000 .

[38]  M. Michikawa,et al.  Midkine Inhibits Caspase‐Dependent Apoptosis via the Activation of Mitogen‐Activated Protein Kinase and Phosphatidylinositol 3‐Kinase in Cultured Neurons , 1999, Journal of neurochemistry.

[39]  M. Noda,et al.  A receptor-like protein-tyrosine phosphatase PTPzeta/RPTPbeta binds a heparin-binding growth factor midkine. Involvement of arginine 78 of midkine in the high affinity binding to PTPzeta. , 1999, The Journal of biological chemistry.

[40]  T. Deuel,et al.  Pleiotrophin and midkine, a family of mitogenic and angiogenic heparin-binding growth and differentiation factors. , 1999, Current opinion in hematology.

[41]  T. Muramatsu,et al.  Midkine, a retinoic acid-inducible heparin-binding cytokine, is a novel regulator of intracellular calcium in human neutrophils. , 1997, Biochemical and biophysical research communications.

[42]  S. Kojima,et al.  Dimerization of Midkine by Tissue Transglutaminase and Its Functional Implication* , 1997, The Journal of Biological Chemistry.

[43]  H. Saito,et al.  Expression of syndecan-1 and -3 during embryogenesis of the central nervous system in relation to binding with midkine. , 1997, Journal of biochemistry.

[44]  S. Kojima,et al.  Midkine Enhances Fibrinolytic Activity of Bovine Endothelial Cells (*) , 1995, The Journal of Biological Chemistry.

[45]  I. Thesleff,et al.  Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associated with epithelial-mesenchymal interactions during fetal development and organogenesis. , 1995, Development.

[46]  A. Nakagawara,et al.  A new family of heparin-binding growth/differentiation factors: increased midkine expression in Wilms' tumor and other human carcinomas. , 1993, Cancer research.

[47]  H. Kondoh,et al.  A retinoic acid responsive gene, MK, produces a secreted protein with heparin binding activity. , 1990, Biochemical and biophysical research communications.

[48]  T. Muramatsu,et al.  cDNA cloning and sequencing of a new gene intensely expressed in early differentiation stages of embryonal carcinoma cells and in mid-gestation period of mouse embryogenesis. , 1988, Biochemical and biophysical research communications.

[49]  J. Breslow Apolipoprotein genetic variation and human disease. , 1988, Physiological reviews.

[50]  J. Breslow,et al.  Genetic mutations affecting human lipoprotein metabolism. , 1985, Advances in human genetics.