3P-0771 Bile acid precursors are endogenous ligands for FXR and mediate the negative feedback regulation of bile acid synthesis

3P-0771 Bile acid precursors are endogenous ligands for FXR and mediate the negative feedback regulation of bile acid synthesis

Wednesday October 1, 2003: Poster Session Lipid and lipoprotein metabolism 3P-0770 Circulating malondialdehyde-modified LDL levels are associated wit...

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Wednesday October 1, 2003: Poster Session Lipid and lipoprotein metabolism 3P-0770

Circulating malondialdehyde-modified LDL levels are associated with metabolic syndrome and endothelial dysfunction - Analyses from nuclear magnetic resonance spectroscopy and flow-mediated dilatation

T. Miyazaki, K. Shimada, H. Mokuno, A. Kume, Y. Sato, K. Sumiyoshi, Y. Watanabe, H. Daida. Department of Cardiology, Juntendo University, Tokyo, Japan Objective: Recent studies have suggested circulating malondialdehydemodified LDL (M-LDL) was useful marker for the identification of patients with coronary artery disease (CAD). However, the atherogenic mechanisms of M-LDL have not fully determined. Therefore, we investigated the association between the serum M-LDL levels, LDL size, and endothelial function. Method: M-LDL levels was measured by ELISA and LDL size was measured by nuclear magnetic resonance (NMR) in 30 male patients with CAD and 20 male control subjects. Flow-mediated dilatation (FMD) of the brachial artery was examined by high resolution ultrasonography. Results: Compared with the control group, the CAD group had significantly higher levels of TG, BMI, waist hip ratio (WHR), and significantly lower levels of HDL-C. TC and LDL-C were not significantly different in both groups. The M-LDL levels were significantly higher in the CAD group than in the control group (86.8±26.8 vs. 69.1±18.3 IU/L, p=0.01). The M-LDL levels were positively correlated with TG (r=0.38) and WHR (r=0.38), and negatively correlated with HDL-C (r=-0.36). NMR analysis demonstrated that VLDL-TG and LDL particle concentration were significantly higher, and LDL size was significantly lower in the CAD group than in the control group. The M-LDL levels were positively correlated with VLDL-TG (r=0.43), LDL particle concentration (r=0.42), and negatively correlated with LDL size (r=-0.53). FMD was significantly impaired in the CAD group than in the control group. The M-LDL levels were negatively correlated with FMD (r=0.42). Conclusions: This study indicated that the M-LDL levels may reflect features of metabolic syndrome which is strongly associated with increasing LDL particle concentration and small dense-LDL detected by NMR. The high concentrations of M-LDL may impair endothelial function and play an important role in the development of atherosclerosis. 3P-0771

Bile acid precursors are endogenous ligands for FXR and mediate the negative feedback regulation of bile acid synthesis

T. Nishimaki-Mogami 1 , T. Fujino 1 , M. Une 2 , Y. Sato 1 , M. Tohkin 1 , K. Inoue 1 . 1 National Institute of Health Sciences, Tokyo; 2 Graduate School of Biomedical Sciences, Hiroshima University, Japan

3P-0772

The effect of diet standardization on postprandial chylomicron response

K.M. Slivkoff-Clark, A.P. James, D. Kerr, M.J. Soares, J.C.L. Mamo. Curtin University of Technology, Australia Objective: Postprandial lipid response is influenced by chronic dietary patterns and may be a significant confounder of chylomicron kinetic studies. The aim of this pilot study was to explore the reproducibility of postprandial lipoprotein kinetics following 3-days of dietary standardisation. Methods: Five non-obese normolipidemic males (BMI<27, TG<1.5 mM, T-cholesterol<6.0 mM) were studied. Subjects were required to consume the 3-d standard diet on 2 occasions 4 weeks apart. Following each diet the

postprandial apolipoprotein (apo) B48 and triglyceride (TG) response to a high-fat meal was assessed. The standard diet represents an average dietary pattern and allowed subjects limited freedom to choose from food/snack options. In total the diet provided 9800 kJ, 30% of energy as fat, 52% of energy from carbohydrate and 15.3% of energy from protein. Results: We observed similar baseline and postprandial lipid and apo B48 values between visits (Table 1). Table 1: Fasting apo B48, lipids and postprandial apo B48 results

Fasting apo B48 (µg/mL) Fasting TG (mM) Fasting T-cholesterol (mM) Apo B48 incremental AUC (µg.mL-1 .h)

Visit 1 Mean ± SE

Visit 2 Mean ± SE

8.35 ± 0.67 1.14 ± 0.15 4.49 ± 0.30 18.80 ± 2.18

9.67 ± 1.74 1.41 ± 0.28 5.11 ± 0.18 20.34 ± 7.36

Following diet standardisation the average difference in the postprandial response of apo B48 between visits was 8% compared to a 56% difference observed previously in a group of subjects who’s diet had not been standardised. Conclusion: Postprandial lipemia is influenced by chronic dietary behaviour and may confound interpretation of response to a single meal. In normolipidemic subjects, standardising food intake for 3 days appears to correct for the influence of habitual diet on postprandial lipemia. 3P-0773

The basal level of serum remnant-like particles is an important determinant in the effect of regular aerobic exercise on the reduction of serum remnants

Y. Takanami 1 , Y. Kawai 1 , F. Kinoshita 2 , O. Mohira 2 , T. Shimomitsu 1 . 1 Dept of Preventive Med & Public Health, Tokyo Medical University; 2 Wakayama Wellness Foundation, Japan In the present study, we assessed the hypothesis that physically active life-style could reduce remnant lipoproteins through the improvement of triglyceride (TG) rich lipoprotein metabolism especially in the subjects with high serum remnants levels. 46 sedentary subjects (mean±SD, 50.6±5.7y, 25 males and 21 females) were instructed to perform 30-60 min of aerobic exercise training such as brisk walking at least 3 times a week for 3 months. We drew blood from the subjects early in the morning after a 12-hour overnight fast once at baseline, once after a month, and once after 3 months of exercise training period (EX). Serum lipids and maximum oxygen uptake (VO2 max) were analyzed. We assigned the subjects to three groups according to their serum remnant-like lipoprotein particles cholesterol (RLP-C) levels at baseline (high: 7.6-31.9 mg/dl, middle: 5.5-7.5 mg/dl, low: 2.1-5.2 mg/dl). A significant increase in VO2 max was detected in all groups after the 3-month of EX. Although there was no significant change in RLP-C in the low group (baseline, one month after, 3 months after: 4.0±0.9, 5.1±2.4, 4.1±1.5 mg/dl), RLP-C of the middle group showed a significant reduction after the 3-month of EX (6.5±0.8, 7.2±4.3, 4.7±1.3 mg/dl; p<0.01). In the high group, a significant decrease in RLP-C was observed from earlier stage, after one month and 3-month of EX (15.2±7.9, 9.7±4.0, 8.4±4.1 mg/dl; p<0.01). The reduction of RLP-C was remarkable in comparison with that of serum TG in the middle (119±27, 123±60, 95±26 mg/dl) and the high group (186±81, 133±60, 158±71 mg/dl). In conclusion, regular aerobic exercise is a beneficial means to reduce serum RLP-C especially for the subjects having a higher remnant level. 3P-0774

Serum RLP-cholesterol levels in hypertriglyceridemia associated with hyperalphalipoproteinemia

M. Okazaki 1 , I. Sakurabayashi 2 , K. Nakajima 3 , T. Nakano 3 . 1 Tokyo Medical Dental Univ.; 2 Jichi Medical School; 3 Japan Immunoresearch Laboratories Co., Ltd., Japan Objective: High serum RLP-C levels have been reported to be highly associated with hypertriglyceridemia. Here we have studied serum RLP-C levels among hypertriglyceridemic subjects associated with hyper-α-lipoproteinemia (HDL-C>80 mg/dL), which were detected as rather rare cases than the cases with hypo-α-lipoproteinemia. Methods: Among 510 hyperlipidemic cases whose serum lipid levels were TC>240 mg/dL and TG>200 mg/dL were chosen for this study at health check-ups in Urawa, Japan. Forty three cases (8.4%) (Group A) were HDL-C below 40 mg/dL and 441 cases (86.5%) (Group B) between 41 to 80 mg/dL. Twenty six cases (5.1%) (Group C) were HDL-C levels above 80 mg/dL. Twenty two healthy pregnancy with high serum TG and HDL-C were studied.

XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan

WEDNESDAY

Bile acid synthesis from cholesterol is tightly regulated via a feedback mechanism mediated by farnesoid X receptor (FXR), a nuclear receptor that is activated by bile acids. In the main synthetic pathway (the classic pathway), synthesis is initiated by a series of cholesterol ring modification, followed by oxidation of the side chain. We show that C27 -intermediates of the latter steps, bile alcohols and C27 -bile acids (or higher bile acids), are highly efficacious ligands for FXR. Using transient transfections with an FXR- responsive element-driven luciferase construct, these precursors were shown to activate FXR as potently as the most potent physiological ligand, chenodeoxycholic acid. As ligands, these precursors induced the interaction of FXR with a peptide derived from coactivator SRC-1 in vitro. Treatment of cultured rat hepatocytes or HepG2 cells with these precursors increased the short heterodimer partner (SHP) mRNA level and repressed the levels of rate-limiting cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) mRNA. These results provide evidence that bile acid synthesis is negatively regulated by intermediate bile alcohols and C27 -bile acids as well as by bile acid end-products.

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