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Increased Phospholipid Transfer Protein Activity Associated with the Impaired Cellular Cholesterol Efflux in Type 2 Diabetic Subjects with Coronary Artery Disease

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Increased Phospholipid Transfer Protein Activity Associated with the Impaired Cellular Cholesterol Efflux in Type 2 Diabetic Subjects with Coronary Artery Disease Tohoku J. Exp. Med., 2007,Cholesterol 213, 129-137 Efflux and PLTP Activity in Diabetes with CAD 129 Increased Phospholipid Transfer Protein Activity Associated with the Impaired Cellular Cholesterol Efflux in Type 2 Diabetic Subjects with Coronary Artery Disease 1,2 2 2 2 3 NEBIL ATTIA, AMEL NAKBI, MAHA SMAOUI, RAJA CHAABA, PHILIPPE MOULIN, 4 4 5 SONIA HAMMAMI, KHALDOUN BEN HAMDA, FRANÇOISE CHANUSSOT and 2 MOHAMED HAMMAMI 1Biology Department, Faculty of Sciences, University November 7th at Carthage, Bizerte, Tunisia 2Biochemistry Laboratory, UR 08-39, Faculty of Medicine, University of Monastir, Monastir, Tunisia 3U11 Cardiovascular Unit, Louis Pradel Hospital and INSERM U585, Lyon, France 4Departments of Internal Medicine (SH) and Cardiology (KBH), Monastir Hospital, Monastir, Tunisia 5INSERM U476, Faculty of Medecine la Timone, University Aix-Marseille II, Marseille, France ATTIA, N., NAKBI, A., SMAOUI, M., CHAABA, R., MOULIN, P., HAMMAMI, S., HAMDA, K.B., CHANUSSOT, F. and HAMMAMI, M. Increased Phospholipid Transfer Protein Activity Associated with the Impaired Cellular Cholesterol Efflux in Type 2 Diabetic Subjects with Coronary Artery Disease. Tohoku J. Exp. Med., 2007, 213 (2), 129-137 ── Reverse cholesterol transport (RCT) is the pathway, by which the excess of cholesterol is removed from peripheral cells to the liver. An early step of RCT is the efflux of free cholesterol from cell membranes that is mediated by high-density lipoproteins (HDL). Phospholipid transfer protein (PLTP) transfers phospholipids between apolipoprotein-B-containing lipo- proteins (i.e., chylomicrons and very low-density lipoproteins) and HDL. PLTP contrib- utes to the HDL maturation and increases the ability of HDL to extract the cellular choles- terol. It is known that RCT is impaired in type 2 diabetic patients, especially when cardiovascular complication is associated with. In this study, we measured the serum capacity that promotes cellular cholesterol efflux and the plasma PLTP activity in type 2 diabetic patients with coronary artery disease (CAD) (n = 35), those without CAD (n = 24), and 35 healthy subjects as a sex- and age-matched control. In patients with CAD, plasma triglyceride level was higher compared to controls (p < 0.01) and HDL-cholesterol was lower (p < 0.01 vs control and the patients without CAD). In diabetic patients with or without CAD, PLTP activity was consistently increased, compared to controls, while cellu- lar cholesterol efflux activity was decreased by 20% (p < 0.001) or 13.5% (p < 0.01), respectively. In conclusion, plasma PLTP activity was increased in type 2 diabetic patients with or without CAD, which could impair cellular cholesterol removal and might acceler- ate atherosclerosis in diabetic patients. ──── cholesterol efflux; PLTP activity; Type 2 diabetes; coronary artery disease © 2007 Tohoku University Medical Press Received May 2, 2007; revision accepted for publication August 20, 2007. Correspondence: Dr. Nebil Attia, Ph.D., Department of Biology, Sciences Faculty of Bizerte, 7021 Jarzouna, Tunisia. e-mail: [email protected] 129 130 N. Attia et al. Cholesterol Efflux and PLTP Activity in Diabetes with CAD 131 Type 2 diabetes (non-insulin dependent) is Few studies have described the serum capac- associated with cardiovascular risk including high ity to promote cellular cholesterol in type 2 diabe- plasma triglycerides (TG) and low high-density tes with coronary artery disease (CAD). It was lipoprotein cholesterol (HDL-C) (West et al. reported that LpAI: AII particles are remarkably 1983). The negative relationship between the involved at this step of RCT, especially when type HDL-C concentration and the risk of cardiovascu- 2 and CAD coexist (Taskinen 1990; Cavallero et lar disease (Gordon and Rifkind 1989) is thought al. 1995; Syvänne et al. 1996). to be attributable, at least in part, to the key role All these data show that the PLTP is associ- of HDL in reverse cholesterol transport (RCT) ated with the atherosclerosis, but do not prove from peripheral tissues to the liver for excretion that PLTP is responsible for the impairment of the (Fielding and Fielding 1995; Tall and Wang cellular cholesterol efflux in diabetes. In this 2000). The first step of RCT is efflux of free cho- work we attempted to clarify the role of the PLTP lesterol from cell membranes to the extracellular in the extraction of cholesterol from Fu5AH rat medium. Numbers of studies have established hepatoma cells in type 2 diabetes with or without that at least three mechanisms are involved: a CAD. non-specific and relatively inefficient aqueous diffusion pathway which operates in all cells, and PATIENTS AND METHODS two regulated pathways, which are modulated by Patients phospholipid (PL)-containing acceptor particles A total of 59 Tunisian patients with diabetes melli- (such as HDL) or lipid-poor apolipoproteins (apo) tus (35 with CAD and 24 without; respectively D+C+ (Yancey et al. 2003). On the other hand, it has and D+C- groups) were recruited in the Department of been shown that plasma preβ-HDL is elevated in Cardiology and Internal Medicine in the University hypertriglyceridemia (Ishida et al. 1987). These Hospital of Monastir, and 35 healthy subjects served as a particles are considered to be the initial acceptors control group (age range: 40-74 years). Written or oral of cellular cholesterol (Castro and Fielding 1988), consent was obtained from all the patients and healthy and cellular cholesterol efflux, measured using subjects before the study. Written consents were not pos- Fu5AH cells, is positively correlated with sible in all cases because the majority of eligible subjects preβ-HDL (Dullart and Van Tol 2001). One of in our study were unable to read or write. The protocol processes of cellular cholesterol efflux is mediated was approved by the Ethics Committee of Monastir by the ATP-binding cassette transporter A1 Hospital (CELHM). (ABCA1). The diagnosis of diabetes was based on a previous The early step of RCT is also controlled by history of diabetes on American Diabetes Association phospholipid transfer protein (PLTP) which trans- criteria (The Expert Committee on the Diagnosis and fers PLs between apoB-containing lipoproteins Classification of Diabetes Mellitus 1997). The diabetic and HDL, and catalyzing HDL conversion reac- patients without CAD had a normal ECG and no history tions. PLTP may therefore participate in RCT and or clinical signs of CAD with a maximal negative exer- cise test. The patients with CAD were defined as those cholesterol efflux by regenerating nascent discoi- having clinical history of stable angina pectoris, previous dal HDL (ndHDL) during HDL conversion, and acute coronary syndromes with or without ST segment facilitating the lipidation of ndHDL in the suben- elevation, and this CAD was confirmed by coronary dothelial space (Ohashi et al. 2005). At the same angiography. The extent of CAD was assessed by the time, PLTP interacts with and stabilizes ABCA1, number of coronary vessels with more than 50% reduc- and enhances cholesterol efflux from cells (Oram tion in the luminal diameter. Exclusion criteria were et al. 2003). Generally, PLTP is now considered taking insulin or lipid lowering drugs (apart from a statin as an atherosclerosis risk factor in animals taking by most of CAD patients), having a renal or liver (Vikstedt et al. 2007) and human with obesity, failure or thyroid disease, alcohol consumption 3 days diabetes and/or coronary artery disease (Jiang et prior to the study or less, a body mass index (BMI) more al. 2002; Cheung et al. 2006; de Vries et al. 2006). than 35 kg/m² and glycated hemoglobin (Hb A1c) more 130 N. Attia et al. Cholesterol Efflux and PLTP Activity in Diabetes with CAD 131 than 12%. Plasma triglyceride concentration was under ments, cells were seeded in six-well plates at a density of 10 mmol/l in type 2 diabetes and under 2.3 mmol/l in 45 000-50 000 cells per well and grown in MEM wit 5% healthy controls. Post menopausal women had no hor- calf serum for two days. Radiolabeled cholesterol mone replacement therapy. Hypertension in diabetic ([1,2-3H]cholesterol, TRK 330, Amersham, France) was population was diagnosed according to predetermined added to the cells: a tracer amount was first mixed into blood pressure level (systolic blood pressure > 130 25% calf serum in MEM, then diluted with MEM to 5% mmHg and/or diastolic blood pressure level > 85 mmHg) final serum concentration. The cells were grown in the (The Sixth Report of the Joint National Committee on presence of radiolabeled for two more days to obtain prevention, detection, evaluation, and treatment of high confluent monolayers, and to allow for radiolabeled cho- blood pressure 1997) or the patients were on antihyper- lesterol to exchange into all cellular pool. The labeling tensive therapy. Body mass index (BMI) was calculated medium was finally replaced by MEM containing 0.5% using the formula: weight (kg)/height² (m²). Obesity was bovine serum albumin for 18 to 20 hrs before measuring defined as BMI > 30 kg/m². The waist-to-hip ratio was of cholesterol efflux to further ensure that pools were calculated from measurements of the waist circumfer- equilibrated. ence taken at the midpoint between the umbilicus and The capacity of serum to promote efflux from the xiphoid and the hip circumference, at the widest point labeled cells was assayed by adding individual samples around the hips, respectively. Blood samples were drawn of the patients’ serum to a final concentration of 5% and after subjects had fasted overnight (12 hrs) into tubes quantifying the amount of radiolabeled cholesterol containing EDTA and plasma was immediately separated release over 4 hrs. At the end of the efflux period, the by centrifugation. Samples used for PLTP activity or medium was collected into ice-chilled tubes and centri- cholesterol efflux were immediately stored at −80°C for fuged in the cold for 5 min at 2,000 rpm to remove cells.
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