- Email: [email protected]
W12.313 Cytotoxicity of postprandial hypertriglyceridemic plasma to cultured human macrophages
72
W13
Tentor
Workshops Cellular lipid and lipoprotein transport
Results: The distribution of fasting serum apo B-48 levels in NL subjects varied widely, ranging fi'om less than 1 to over 24 ~g/ml (mean, 5.2 4- 3.8, median, 3.9, and 95 percentile was less than 13). In total 588 subjects, FPG (102.5-t-31.9 mg/dl vs 95.5-t-17.6, p<0.05), HbAlc (5.4-t-1.0% vs 5.0-t-0.7, p<0.01), BMI (24.4-t-2.8 kg/m 2 vs 23.4-t-3.0, p<0.01), total cholesterol, triglycerides, and HDL-C levels were significantly higher in apo B-48> 13 ~g/ml group than those in apo B-48 <13 ~g/ml group. Serum apo B-48 levels were significantly higher in FPG> 110 mg/dl and BMI_>25 kg/m2 groups than those in FPG< 110 mg/dl and BMI<25 kg/m 2 gl"oups, respectively, and tended to be higher (p=0.08) in subjects with HbAlc>5.8% than subjects with HbAlc<5.8%. In 335 NL subjects, HbAlc level was significantly higher in subjects with apo B-48>8.5 ~g/ml (85 percentile) than those with apo B-48<8.5 ~g/ml. Serum apo B-48 levels were significantly higher in those with F P G > l l 0 mg/dl than those with F P G < l l 0 mg/dl. In male diabetic inpatients (n=25), an average of two weeks admission resulted in a significant decrease (p<0.05) in serum apo B-48 levels in association with a marked improvement of FPG and HbAlc. Taking CR accumulation into consideration, serum TG levels in diabetic patients should be set about 15% lower than the normal levels detelxnined in non-diabetic subjects. Conclusions: In conclusion, the levels of CR were increased in diabetic patients even if they were norrnolipidemic, predisposing the patients to CHD.
~
IN VIVO DIFFERENCES BETWEEN THE SEXES IN THE METABOLISM OF TRIGLYCERIDE-RICH LIPOPROTEINS
J. Tentor, M. Cruz, L. Harada, M. Danelon, D. Kaplan, L. Castilho, R. Nakamura, E. de Faria. Unicamp, Campinas, Brazil Objective: We investigated in which phase(s) of the lipemic response to a fat-rich diet sex-dependent differences occur. Methods: Fourty-two normolipidemic volunteers aged 19-45y, 22 men (M) and 20 women (W) were matched according to age, body mass index, waist, blood pressure, diet and physical activity. After 12h of fast the participants received a milk-shake containing 40g of fat/m2 of body surface area and serial blood samples were collected for serum triglyceride (TG) measurements. Data are presented as averages -4- SD. Rsesults: The average area under the triglyceride curves (AUC, mg/dL.8h) were 748-4-281, W; 1079-4-468, M, (p=0.02) and the average incremental area under the curves (AUIC) 230-4-145, W; 436-4-284, M, (p=0.005), both larger in men. The higher triglyceridemia (mg/dL) in the men occmved at the 2nd (p=0.01), 4th (p=0.04) and 6th (p=0.01) hours. The post-absorptive triglyceride peak, 4th h, was 50% higher in men (M=160-4-84) than in women (W=107-4-48). Also the ascending and descending curve slopes were both higher in M (p= 0.030 and p=0.005, respectively). Conclusions: We provided data indicating that the sex differences in lipemia are due to increased production of triglyceride rich lipoproteins, despite theft" increased catabolism. This fact could contribute to the higher risk of coronary artery disease in men.
•
EFFECTS OF ROSUVASTATIN ON FASTING AND POSTPRANDIAL LIPIDS IN COMBINED HYPERLIPIDEMIC MALE PATIENTS WITH PREMATURE CORONARY SCLEROSIS
A. van Oostrom, A. Alipour, T. Sijmonsma, T. Rabelink, H. Plokker, P. de Jaegere, M. Castro Cabezas. Dept. of Vasc. Med., UMC Utrecht and Heart
Lung Institute Utrecht, Utrecht, the Netherlands Objective- Postprandial hyperlipidemia is associated with prematme coronary artery disease (CAD) and improves by statins. We investigated the effects of a novel statin, rosuvastatin, on postprandial lipemia in a group of 20 male patients (50-4-4 years) with premature CAD. Methods- By self-determined daylong capillary triglycerides (TGc), dose-dependent effects were investigated after rosuvastatin 20mg/d, followed by 40rag/d, both for four weeks. Standardized oral fat-loading tests (OFLT) were performed before and after 40mg/d ~eatment. Twenty ageand waist-matched healthy controls served as a reference group. Total areas under the postprandial curves (AUC) were calculated and lipoproteins during the OFLT's were subfi'actionated by ultracentrifugation. Results- Rosuvastatin 20mg/d improved fasting LDL-cholesterol (-52%: to 2.1-4-0.5 raM, P<0.001), plasma TG (-37%: to 1.42-4-0.47 raM, P<0.001), apolipoprotein B (-37%: to 0.79-4-0.16, P<0.001) and HDL-cholesterol
(+25%: to 1.16-4-0.27 mM, P<0.01). Daylong triglyceridemia (TGc-AUC) was reduced by 33% (P<0.001) after 20 mg rosuvastatin, but remained higher than the reference gl"oup. Rosuvastatin 40mg/d did not show significant additional effects on fasting lipids or daylong TGc. Rosuvastatin 40mg/d reduced TG-AUC after the OFLT by 23% (P<0.005), reaching reference values. Wheleas strong and significant reductions in the fasting and postprandial cholesterol content of chylomicrons, VLDL1 and VLDL2 fi'actions were achieved, the TG reduction in these lipoproteins was less pronounced. EFFECTS ON PLASMA AND IW12.3121ATORVASTATIN MARGINATED APOB48 AND B100 IN TRIGLYCERIDE RICH LIPOPROTEINS IN FCHL C. Verseyden, S. Meijssen, M. Castro Cabezas. Dept. Vascular Medicine,
University Medical Center Utrecht, Utrecht, The Netherlands Background: Large TG-rich lipoproteins (TRL's) cfl'culate in the blood but may also be present in a marginated pool, probably attached to the endothelium. It is unknown whether statins can influence this marginated pool in vivo in humans. Intravenous fat tests were performed in FCHL subjects, before and after atorvastatin, and in controls in order to investigate whether acute apoB increases in TRL fi'actions would occur, potentially reflecting release of this TRL's fi'om a marginated pool. Methods: After 12 hours fasting, a bolus injection with Intralipid ® 10% was given to 12 FCHL patients before and after 16 weeks atorvastatin treatment. Twelve carefully-matched controls were included. During 60 minutes post-injection, apoB48, apoB100 and lipids were measured in TRL's. Results: Fasting apoB100 in all TRL fi'actions were 2 to 3-fold higher in untreated FCHL compared to controls. ApoB48 concentrations in chylomicron fi'actions increased significantly within 10 minutes in FCHL before and after treatment, but not in controls. ApoB100 increased significantly in the chylomicron fi'actions in untreated FCHL and in controls, but not in FCHL after treatment. In VLDL1, apoB100 increased only in untreated FCHL. In VLDL2, apoB100 did not change in any group. Conclusion: These data show that increasing the number of cfl'culating TRL's by chylomicron-like particles, results in increased plasma apoB-TRL's, probably by acute release fi'om a marginated pool. This is a physiological process occurring in FCHL and in healthy normolipidemics, but is more pronounced in the former. Atorvastatin decreases the number of marginated TRL particles in FCHL which is a novel anti-atherogenic mechanism.
W12.313 ] CYTOTOXICITY OF POSTPRANDIAL HYPERTRIGLYCERIDEMIC PLASMA TO CULTURED HUMAN MACROPHAGES A. Wehinger, W. Schgoer, R. Gander, E Eller, A. Ritsch, J. Patsch, B. Foeger. Department of Medicine, University of Innsbruck, Innsbruck,
Austria Postprandial (pp) lipemia is an independent risk factor for atherosclerosis. One of several mechanisms to account for this could be damage to arterial cells during lipolysis. Thus, we tested whether addition of fasting plasma, preincubated ex vivo with bovine LPL, would compromise viability of cultured human macrophages, as assessed by trypan blue exclusion. Not~ motfiglyceridemic (NTG) plasma, with o1" without LPL induced a roughly similar amount of cell damage [0,194- 0,32% (n=10) vs. 0,074- 0,13% (n=10), p=0,35]. In contrast, in hypertriglycefidemic (HTG) plasma addition of LPL led to an almost complete cytolytic effect [(3,184- 0,99% (n=10) vs. 98,24- 1,69% (n=10), p<0,001]. In order to test whether these findings also pertain to the pp phase in humans we challenged two NTG and one HTG patients using a standardised liquid fat meal (Patsch JR, PNAS 80:1449). In two NTG patients, cell damage induced by postheparin plasma (6h pp) was roughly equivalent to that of preheparin plasma. In contrast, in the HTG patient cell damage induced by postheparin plasma greatly exceeded that of preheparin plasma (2,34- 1,13% (n=10) vs. 0,054- 0,1% (n=10), p<0,001). Conclusion: Lipolysis is cytotoxic to human macrophages and may dh'ectly promote atherogenesis.
74th EAS Congress, 17-20 April 2004, Seville, Spain
W13
Tentor
Workshops Cellular lipid and lipoprotein transport
Results: The distribution of fasting serum apo B-48 levels in NL subjects varied widely, ranging fi'om less than 1 to over 24 ~g/ml (mean, 5.2 4- 3.8, median, 3.9, and 95 percentile was less than 13). In total 588 subjects, FPG (102.5-t-31.9 mg/dl vs 95.5-t-17.6, p<0.05), HbAlc (5.4-t-1.0% vs 5.0-t-0.7, p<0.01), BMI (24.4-t-2.8 kg/m 2 vs 23.4-t-3.0, p<0.01), total cholesterol, triglycerides, and HDL-C levels were significantly higher in apo B-48> 13 ~g/ml group than those in apo B-48 <13 ~g/ml group. Serum apo B-48 levels were significantly higher in FPG> 110 mg/dl and BMI_>25 kg/m2 groups than those in FPG< 110 mg/dl and BMI<25 kg/m 2 gl"oups, respectively, and tended to be higher (p=0.08) in subjects with HbAlc>5.8% than subjects with HbAlc<5.8%. In 335 NL subjects, HbAlc level was significantly higher in subjects with apo B-48>8.5 ~g/ml (85 percentile) than those with apo B-48<8.5 ~g/ml. Serum apo B-48 levels were significantly higher in those with F P G > l l 0 mg/dl than those with F P G < l l 0 mg/dl. In male diabetic inpatients (n=25), an average of two weeks admission resulted in a significant decrease (p<0.05) in serum apo B-48 levels in association with a marked improvement of FPG and HbAlc. Taking CR accumulation into consideration, serum TG levels in diabetic patients should be set about 15% lower than the normal levels detelxnined in non-diabetic subjects. Conclusions: In conclusion, the levels of CR were increased in diabetic patients even if they were norrnolipidemic, predisposing the patients to CHD.
~
IN VIVO DIFFERENCES BETWEEN THE SEXES IN THE METABOLISM OF TRIGLYCERIDE-RICH LIPOPROTEINS
J. Tentor, M. Cruz, L. Harada, M. Danelon, D. Kaplan, L. Castilho, R. Nakamura, E. de Faria. Unicamp, Campinas, Brazil Objective: We investigated in which phase(s) of the lipemic response to a fat-rich diet sex-dependent differences occur. Methods: Fourty-two normolipidemic volunteers aged 19-45y, 22 men (M) and 20 women (W) were matched according to age, body mass index, waist, blood pressure, diet and physical activity. After 12h of fast the participants received a milk-shake containing 40g of fat/m2 of body surface area and serial blood samples were collected for serum triglyceride (TG) measurements. Data are presented as averages -4- SD. Rsesults: The average area under the triglyceride curves (AUC, mg/dL.8h) were 748-4-281, W; 1079-4-468, M, (p=0.02) and the average incremental area under the curves (AUIC) 230-4-145, W; 436-4-284, M, (p=0.005), both larger in men. The higher triglyceridemia (mg/dL) in the men occmved at the 2nd (p=0.01), 4th (p=0.04) and 6th (p=0.01) hours. The post-absorptive triglyceride peak, 4th h, was 50% higher in men (M=160-4-84) than in women (W=107-4-48). Also the ascending and descending curve slopes were both higher in M (p= 0.030 and p=0.005, respectively). Conclusions: We provided data indicating that the sex differences in lipemia are due to increased production of triglyceride rich lipoproteins, despite theft" increased catabolism. This fact could contribute to the higher risk of coronary artery disease in men.
•
EFFECTS OF ROSUVASTATIN ON FASTING AND POSTPRANDIAL LIPIDS IN COMBINED HYPERLIPIDEMIC MALE PATIENTS WITH PREMATURE CORONARY SCLEROSIS
A. van Oostrom, A. Alipour, T. Sijmonsma, T. Rabelink, H. Plokker, P. de Jaegere, M. Castro Cabezas. Dept. of Vasc. Med., UMC Utrecht and Heart
Lung Institute Utrecht, Utrecht, the Netherlands Objective- Postprandial hyperlipidemia is associated with prematme coronary artery disease (CAD) and improves by statins. We investigated the effects of a novel statin, rosuvastatin, on postprandial lipemia in a group of 20 male patients (50-4-4 years) with premature CAD. Methods- By self-determined daylong capillary triglycerides (TGc), dose-dependent effects were investigated after rosuvastatin 20mg/d, followed by 40rag/d, both for four weeks. Standardized oral fat-loading tests (OFLT) were performed before and after 40mg/d ~eatment. Twenty ageand waist-matched healthy controls served as a reference group. Total areas under the postprandial curves (AUC) were calculated and lipoproteins during the OFLT's were subfi'actionated by ultracentrifugation. Results- Rosuvastatin 20mg/d improved fasting LDL-cholesterol (-52%: to 2.1-4-0.5 raM, P<0.001), plasma TG (-37%: to 1.42-4-0.47 raM, P<0.001), apolipoprotein B (-37%: to 0.79-4-0.16, P<0.001) and HDL-cholesterol
(+25%: to 1.16-4-0.27 mM, P<0.01). Daylong triglyceridemia (TGc-AUC) was reduced by 33% (P<0.001) after 20 mg rosuvastatin, but remained higher than the reference gl"oup. Rosuvastatin 40mg/d did not show significant additional effects on fasting lipids or daylong TGc. Rosuvastatin 40mg/d reduced TG-AUC after the OFLT by 23% (P<0.005), reaching reference values. Wheleas strong and significant reductions in the fasting and postprandial cholesterol content of chylomicrons, VLDL1 and VLDL2 fi'actions were achieved, the TG reduction in these lipoproteins was less pronounced. EFFECTS ON PLASMA AND IW12.3121ATORVASTATIN MARGINATED APOB48 AND B100 IN TRIGLYCERIDE RICH LIPOPROTEINS IN FCHL C. Verseyden, S. Meijssen, M. Castro Cabezas. Dept. Vascular Medicine,
University Medical Center Utrecht, Utrecht, The Netherlands Background: Large TG-rich lipoproteins (TRL's) cfl'culate in the blood but may also be present in a marginated pool, probably attached to the endothelium. It is unknown whether statins can influence this marginated pool in vivo in humans. Intravenous fat tests were performed in FCHL subjects, before and after atorvastatin, and in controls in order to investigate whether acute apoB increases in TRL fi'actions would occur, potentially reflecting release of this TRL's fi'om a marginated pool. Methods: After 12 hours fasting, a bolus injection with Intralipid ® 10% was given to 12 FCHL patients before and after 16 weeks atorvastatin treatment. Twelve carefully-matched controls were included. During 60 minutes post-injection, apoB48, apoB100 and lipids were measured in TRL's. Results: Fasting apoB100 in all TRL fi'actions were 2 to 3-fold higher in untreated FCHL compared to controls. ApoB48 concentrations in chylomicron fi'actions increased significantly within 10 minutes in FCHL before and after treatment, but not in controls. ApoB100 increased significantly in the chylomicron fi'actions in untreated FCHL and in controls, but not in FCHL after treatment. In VLDL1, apoB100 increased only in untreated FCHL. In VLDL2, apoB100 did not change in any group. Conclusion: These data show that increasing the number of cfl'culating TRL's by chylomicron-like particles, results in increased plasma apoB-TRL's, probably by acute release fi'om a marginated pool. This is a physiological process occurring in FCHL and in healthy normolipidemics, but is more pronounced in the former. Atorvastatin decreases the number of marginated TRL particles in FCHL which is a novel anti-atherogenic mechanism.
W12.313 ] CYTOTOXICITY OF POSTPRANDIAL HYPERTRIGLYCERIDEMIC PLASMA TO CULTURED HUMAN MACROPHAGES A. Wehinger, W. Schgoer, R. Gander, E Eller, A. Ritsch, J. Patsch, B. Foeger. Department of Medicine, University of Innsbruck, Innsbruck,
Austria Postprandial (pp) lipemia is an independent risk factor for atherosclerosis. One of several mechanisms to account for this could be damage to arterial cells during lipolysis. Thus, we tested whether addition of fasting plasma, preincubated ex vivo with bovine LPL, would compromise viability of cultured human macrophages, as assessed by trypan blue exclusion. Not~ motfiglyceridemic (NTG) plasma, with o1" without LPL induced a roughly similar amount of cell damage [0,194- 0,32% (n=10) vs. 0,074- 0,13% (n=10), p=0,35]. In contrast, in hypertriglycefidemic (HTG) plasma addition of LPL led to an almost complete cytolytic effect [(3,184- 0,99% (n=10) vs. 98,24- 1,69% (n=10), p<0,001]. In order to test whether these findings also pertain to the pp phase in humans we challenged two NTG and one HTG patients using a standardised liquid fat meal (Patsch JR, PNAS 80:1449). In two NTG patients, cell damage induced by postheparin plasma (6h pp) was roughly equivalent to that of preheparin plasma. In contrast, in the HTG patient cell damage induced by postheparin plasma greatly exceeded that of preheparin plasma (2,34- 1,13% (n=10) vs. 0,054- 0,1% (n=10), p<0,001). Conclusion: Lipolysis is cytotoxic to human macrophages and may dh'ectly promote atherogenesis.
74th EAS Congress, 17-20 April 2004, Seville, Spain