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Glycation of Apolipoprotein C1 Impairs Its CETP Inhibitory

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Glycation of Apolipoprotein C1 Impairs Its CETP Inhibitory 1148 Diabetes Care Volume 37, April 2014 Benjamin Bouillet,1,2 Thomas Gautier,2 Glycation of Apolipoprotein C1 Denis Blache,2 Jean-Paul Pais de Barros,2 Laurence Duvillard,2 Jean-Michel Petit,1,2 Impairs Its CETP Inhibitory Laurent Lagrost,2 and Bruno Verges` 1,2 Property: Pathophysiological Relevance in Patients With Type 1 and Type 2 Diabetes OBJECTIVE Apolipoprotein (apo)C1 is a potent physiological inhibitor of cholesteryl ester transfer protein (CETP). ApoC1 operates through its ability to modify the elec- trostatic charge at the lipoprotein surface. We aimed to determine whether the inhibitory ability of apoC1 is still effective in vivo in patients with diabetes and whether in vitro glycation of apoC1 influences its electrostatic charge and its CETP inhibitory effect. RESEARCH DESIGN AND METHODS ApoC1 concentrations and CETP activity were measured in 70 type 1 diabetic (T1D) patients, 113 patients with type 2 diabetes, and 83 control subjects. The conse- quences of in vitro glycation by methylglyoxal on the electrostatic properties of apoC1 and on its inhibitory effect on CETP activity were studied. An isoelectric analysis of apoC1 was performed in patients with T1D and in normolipidemic- normoglycemic subjects. RESULTS An independent negative correlation was found between CETP activity and apoC1 1Service Endocrinologie, Diabetologie´ et in control subjects but not in patients with diabetes. HbA1c was independently Maladies Metaboliques,´ University Hospital of CARDIOVASCULAR AND METABOLIC RISK associated with CETP activity in T1D patients. In vitro glycation of apoC1 modified Dijon, Dijon, France its electrostatic charge and abrogated its ability to inhibit CETP activity in a 2INSERM, UMR 866, University of Bourgogne, concentration-dependent manner. The isoelectric point of apoC1 in T1D patients Dijon, France was significantly lower than that in control subjects. Corresponding author: Benjamin Bouillet, [email protected]. CONCLUSIONS Received 25 June 2013 and accepted 5 December 2013. The ability of apoC1 to inhibit CETP activity is impaired in patients with diabetes. Glycation of apoC1 leads to a change in its electrostatic properties that might Clinical trial reg. no. NCT00953498, clinicaltrials .gov. account, at least in part, for a loss of constitutive CETP inhibition and an increase in © 2014 by the American Diabetes Association. plasma CETP activity in patients with diabetes. See http://creativecommons.org/licenses/by- Diabetes Care 2014;37:1148–1156 | DOI: 10.2337/dc13-1467 nc-nd/3.0/ for details. care.diabetesjournals.org Bouillet and Associates 1149 Apolipoprotein (apo)C1, a small, basic might impair its ability to inhibit CETP serum separation within 2 h after apolipoprotein mainly produced by the activity. We also hypothesized that the collection. The plasma was divided into liver (1), has been shown to play a physicochemical properties of apoC1 might aliquots and stored at 2808C until significant and complex role in VLDL and be altered in diabetes and might result in biological analysis. HDL metabolism. ApoC1 was found to the impairment of its ability to modulate stimulate hepatic production of VLDL CETP activity. Biochemical Assay Fasting plasma glucose, plasma (2), to inhibit the hydrolysis of VLDL In the first part of the current study, the creatinine, fasting total and HDL-C, and (3–5), and to impair the recognition of association between apoC1 TG were measured on a Vista analyzer VLDL by its cellular receptors (6,7). In concentration and CETP activity was with dedicated reagents (Siemens vivo studies in animal models support assessed in patients with type 1 (T1D) Healthcare Diagnostics, Deerfield, IL). the hypothesis that apoC1 plays a and type 2 (T2D) diabetes in comparison LDL-C was calculated by the Friedewald complex and significant role in both the with healthy normolipidemic- equation when TG levels were ,3.87 accumulation of VLDL particles in the normoglycemic individuals. In the mmol/L (20). When TG levels were blood stream and the reduction in their second part, the effect of in vitro .3.87 mmol/L, LDL-C was measured cholesteryl ester content relative to glycation of apoC1 on its electrostatic directly on the Vista analyzer with triglycerides (TG) (8–11). charge properties was investigated and dedicated reagents (Siemens Healthcare the consequences of this on its ability to In addition, apoC1 has been shown to be a Diagnostics). HbA was measured by inhibit CETP activity were determined. 1c potent inhibitor of cholesteryl ester high-performance liquid chromatography This study provides evidence of the role transfer protein (CETP) activity. In vitro, on a Variant II device (Bio-Rad, of glycation of apoC1 on the loss of the apoC1 inhibits CETP activity when Richmond, CA) (normal range 4–6% CETP inhibitory effect of apoC1 associated with the plasma HDL fraction [20–60 mmol/mol]). (12). The physiological relevance of apoC1 observed in T1D and T2D patients. as a CETP inhibitor has been shown in ApoC1 Concentration RESEARCH DESIGN AND METHODS apoC1–knocked out/human CETP ApoC1 was measured in total plasma transgenic and human apoC1 transgenic/ Study Design and Patients by a specific ELISA using an anti-human Seventy T1D patients, 113 T2D patients, human CETP transgenic mice (13,14). The apoC1 antiserum from rabbit as and 83 normoglycemic-normolipidemic inhibitory effect of apoC1 was found to rely, previously described (21). control subjects were studied. All at least in part, on its ability to modulate subjects were older than 18 years. Measurement of Cholesteryl Ester the electrostatic charge at the HDL surface, Transfer Activity Using a Radioactivity which is recognized as a major determinant Control subjects were not taking any Method of the CETP-lipoprotein interaction and treatment that could interfere with lipoprotein metabolism (lipid-lowering Cholesteryl ester transfer activity in thus of the exchange of core neutral lipids individual plasma samples (25 mLper (15,16). In healthy, normolipidemic agents, anti-HIV agents, combined oral contraceptive pill, corticoids, or retinoic assay) was the measured transfer subjects, the concentration of plasma from [3H]cholesteryl ester–containing apoC1 has been shown to correlate acid), none were pregnant, the fasting , HDL (2.5 nmol per assay) toward negatively with CETP activity and positively glycemia level was 6.1 mmol/L, the TG level was ,1.7 mmol/L, and the LDL endogenous apoB-containing with plasma HDL cholesterol (HDL-C) levels 3 , lipoproteins. [ H]cholesteryl ester– (17,18). In contrast, such relationships cholesterol (LDL-C) level was 4.128 mmol/L. containing HDL was obtained with were not observed in nondiabetic patients HDL from one subject with no lipid with hypertriglyceridemia or combined In patients with diabetes, the presence and no glucose metabolism hyperlipidemia on secondary prevention of microvascular complications abnormalities. (17), suggesting that apoC1 might (retinopathy and nephropathy), was The cholesteryl ester transfer rate was become dysfunctional as a constitutive/ recorded. Three stages were used to calculated from the known specific endogenous CETP inhibitor in high-risk define nephropathy: 0 for no radioactivity of the HDL donors and the populations. nephropathy, 1 for microalbuminuria between30and300mgperday,and2 accumulation of radiolabeled Glycation is known to change side chains for proteinuria .300 mg per day. The cholesteryl esters in the LDL acceptors of reactive amino acids, essentially lysine estimated glomerular filtration rate was after the deduction of blank values and arginine, to form Schiff base and to calculated with the MDRD equation. from control mixtures that were reduce the isoelectric point of proteins incubated at 378C without a plasma (pI) (19). Glycation is a consequence of This prospective single-center study was sample (12,22). hyperglycemia during diabetes. ApoC1 approved by our regional ethics committee. Written informed consent CETP mass concentration was measured contains nine lysine residues and three by a specific ELISA with TP1 anti-CETP arginine residues and is thus likely to be was obtained from all patients before inclusion in this study. antibodies as previously described (23). susceptible to glycation. CETP activity values were calculated as We hypothesized that glycation of apoC1 Plasma Preparation the ratio of the plasma cholesteryl ester might change its electrostatic properties, Blood samples were collected at transfer rate to the plasma CETP mass which are critical in its inhibitory effect, and inclusion and were centrifuged for concentration and were expressed as 1150 ApoC1 Glycation and CETP Inhibitory Property of ApoC1 Diabetes Care Volume 37, April 2014 nanomoles of 3H-CE transferred per from control subjects and patients with P values ,0.05 were considered milligram of CETP per hour. with T1D). statistically significant. Purification of ApoC1 by Chromatofocusing Measurement of Cholesteryl Ester RESULTS ApoC1 was purified from delipidated Transfer Activity by the Fluorescent CETP Activity Correlates With HDL apos by using the chromatofocusing Method ApoC1 Concentrations in Healthy method of Tournier et al. (24). For the in vitro analyses, CETP activity Normolipidemic-Normoglycemic fl was assessed by the uorescent method Control Subjects but Not in Patients Preparation of Lipoproteins as previously described (15). For the With T1D and T2D HDLs were isolated from plasma by measurement of cholesteryl ester Table 1 presents the characteristics of sequential flotation ultracentrifugation,
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