title: Butyrylcholinesterase interactions with amylin may protect pancreatic cells in metabolic syndrome.
abstract: The metabolic syndrome (MetS) is a risk factor for type 2 diabetes mellitus (T2DM). However, the mechanisms underlying the transition from MetS to T2DM are unknown. Our goal was to study the potential contribution of butyrylcholinesterase (BChE) to this process. We first determined the hydrolytic activity of BChE in serum from MetS, T2DM and healthy individuals. The 'Kalow' variant of BChE (BChE-K), which has been proposed to be a risk factor for T2DM, was genotyped in the last two groups. Our results show that in MetS patients serum BChE activity is elevated compared to T2DM patients and healthy controls (P < 0.001). The BChE-K genotype showed similar prevalence in T2DM and healthy individuals, excluding this genotype as a risk factor for T2DM. However, the activity differences remained unexplained. Previous results from our laboratory have shown BChE to attenuate the formation of β-amyloid fibrils, and protect cultured neurons from their cytotoxicity. Therefore, we next studied the in vitro interactions between recombinant human butyrylcholinesterase and amylin by surface plasmon resonance, Thioflavine T fluorescence assay and cross-linking, and used cultured pancreatic β cells to test protection by BChE from amylin cytotoxicity. We demonstrate that BChE interacts with amylin through its core domain and efficiently attenuates both amylin fibril and oligomer formation. Furthermore, application of BChE to cultured β cells protects them from amylin cytotoxicity. Taken together, our results suggest that MetS-associated BChE increases could protect pancreatic β-cells in vivo by decreasing the formation of toxic amylin oligomers.
authors.affiliation: Department of Neurology and Internal Medicine, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Shenhar-Tsarfaty
authors.forename: Tal
authors.initials: T
authors.lastname: Bruck
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Bennett
authors.forename: Tsafrir
authors.initials: T
authors.lastname: Bravman
authors.forename: Einor Ben
authors.initials: EB
authors.lastname: Aassayag
authors.forename: Nir
authors.initials: N
authors.lastname: Waiskopf
authors.forename: Ori
authors.initials: O
authors.lastname: Rogowski
authors.forename: Natan
authors.initials: N
authors.lastname: Bornstein
authors.forename: Shlomo
authors.initials: S
authors.lastname: Berliner
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020349:Surface Plasmon Resonance
chemical_list: D058228:Islet Amyloid Polypeptide; D011994:Recombinant Proteins; D002091:Butyrylcholinesterase
references.citation: Diabetes Care. 2004 Apr;27(4):936-41
references.pmid: 15047652
references.citation: Arch Intern Med. 2006 Jan 9;166(1):106-11
references.pmid: 16401818
references.citation: JAMA. 2002 Jan 16;287(3):356-9
references.pmid: 11790215
references.citation: Scand J Clin Lab Invest. 2008;68(2):123-9
references.pmid: 17852836
references.citation: J Clin Endocrinol Metab. 2004 Aug;89(8):3629-43
references.pmid: 15292279
references.citation: J Clin Endocrinol Metab. 1996 May;81(5):1940-5
references.pmid: 8626861
references.citation: Circulation. 2002 Nov 12;106(20):2533-6
references.pmid: 12427647
references.citation: Acta Anaesthesiol Scand. 2002 Feb;46(2):207-13
references.pmid: 11942873
references.citation: Nat Rev Mol Cell Biol. 2008 Mar;9(3):193-205
references.pmid: 18200017
references.citation: N Engl J Med. 2000 Aug 10;343(6):411-9
references.pmid: 10933741
references.citation: J Clin Psychiatry. 2002;63 Suppl 4:37-41
references.pmid: 11913675
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6020-4
references.pmid: 10339534
references.citation: Chem Biol Interact. 2005 Dec 15;157-158:374-5
references.pmid: 16429499
references.citation: Brain. 2008 Jan;131(Pt 1):109-19
references.pmid: 18056160
references.citation: Circulation. 2005 Nov 15;112(20):3066-72
references.pmid: 16275870
references.citation: J Neurol. 1999 May;246(5):369-70
references.pmid: 10399868
references.citation: Curr Hypertens Rep. 2008 Dec;10(6):440-7
references.pmid: 18959829
references.citation: Mol Endocrinol. 2002 Sep;16(9):2145-54
references.pmid: 12198250
references.citation: Endocr Rev. 2008 Dec;29(7):777-822
references.pmid: 18971485
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8628-33
references.pmid: 16731619
references.citation: IUBMB Life. 2007 Apr-May;59(4-5):332-45
references.pmid: 17505973
references.citation: Neurosci Lett. 1999 Jul 9;269(2):115-9
references.pmid: 10430518
references.citation: Scand J Clin Lab Invest. 2002;62(5):375-83
references.pmid: 12387584
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S74-8
references.pmid: 16432151
references.citation: Protein Sci. 1993 Mar;2(3):404-10
references.pmid: 8453378
references.citation: FEBS J. 2006 Aug;273(15):3614-24
references.pmid: 16884500
references.citation: Int J Obes Relat Metab Disord. 2000 Jun;24(6):695-700
references.pmid: 10878675
references.citation: J Biol Chem. 2004 Jul 9;279(28):29740-51
references.pmid: 15123727
references.citation: J Struct Biol. 2000 Jun;130(2-3):352-62
references.pmid: 10940238
references.citation: Biochem Pharmacol. 1961 Jul;7:88-95
references.pmid: 13726518
references.citation: J Biol Chem. 2009 Jun 19;284(25):17170-17179
references.pmid: 19383604
references.citation: Med Hypotheses. 2007;69(6):1272-6
references.pmid: 17553629
references.citation: Science. 2005 Jan 21;307(5708):380-4
references.pmid: 15662003
references.citation: Circulation. 1999 Sep 21;100(12):1305-10
references.pmid: 10491375
references.citation: Mol Med. 2010 Jul-Aug;16(7-8):278-86
references.pmid: 20464061
references.citation: Acta Neurol Scand. 2000 Dec;102(6):350-3
references.pmid: 11125748
references.citation: Diabetologia. 2001 Dec;44(12):2227-30
references.pmid: 11793025
references.citation: Neuron. 1996 Apr;16(4):881-91
references.pmid: 8608006
references.citation: JAMA. 2001 May 16;285(19):2486-97
references.pmid: 11368702
references.citation: Diabetologia. 2004 Aug;47(8):1437-41
references.pmid: 15258737
references.citation: Cell Death Differ. 2004 Aug;11(8):875-84
references.pmid: 15105833
references.citation: Am J Hypertens. 2000 Jun;13(6 Pt 2):99S-105S
references.pmid: 10921528
references.citation: Diabetes Care. 2003 Nov;26(11):3160-7
references.pmid: 14578255
references.citation: Circulation. 2005 Oct 25;112(17):2735-52
references.pmid: 16157765
references.citation: Chem Biol Interact. 2005 Dec 15;157-158:331-4
references.pmid: 16269140
references.citation: Ann Neurol. 2005 Oct;58(4):623-6
references.pmid: 16037976
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5512-7
references.pmid: 15060281
references.citation: Am J Epidemiol. 2002 Dec 1;156(11):1070-7
references.pmid: 12446265
references.citation: Diabetes. 1999 Feb;48(2):241-53
references.pmid: 10334297
references.citation: Hum Genet. 2000 Apr;106(4):447-52
references.pmid: 10830913