title: A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients.
abstract: Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients.
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC), Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Cubedo
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC), Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Padró
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC), Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Maisa
authors.initials: M
authors.lastname: García-Arguinzonis
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC), Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Vilahur
authors.affiliation: Endocrinology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Inka
authors.initials: I
authors.lastname: Miñambres
authors.affiliation: Endocrinology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Jose María
authors.initials: JM
authors.lastname: Pou
authors.affiliation: Teknon Medical Center, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Ybarra
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC), Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain Cardiovascular Research Chair, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood* / Q000235:genetics / Q000473:pathology; D002402:Cathepsin D / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D008077:Lipoproteins, LDL / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D040901:Proteomics; D051381:Rats
chemical_list: D000596:Amino Acids; D016632:Apolipoprotein A-I; D008077:Lipoproteins, LDL; D002402:Cathepsin D
keywords: diabetes; hyperglycemia; low density lipoprotein; proteomics