- Email: [email protected]
4.P.370 Cholesterol transport between cells and high density lipoprotein subfractions from obese and lean subjects
Thursday 9 October 1997: Posters HDL/reverse cholesterol transport
374
P < 0.01 Profile A n = 22 Profile B n= 7 Controls n = 7
HDL2/HDL3 1 .30 t 0 .28* 0.75 t 0.23 0.65 f 0.23
LpA-I/LpA-I:A-II 1 .01 t 0.2* 0 .69 t 0 .2 0 .71 t 0 .1
HDL2b % 41 .9 t 6* 26 .3 t 5 27 .6 f 4
HDL3a 21 t 4 32 t 3 { 28 f 4
Moreover, the HALP profile A had elevated HDL2b levels whereas profile B had elevated HDL3a levels . CETP mass and activities were higher in patients than in control subjects, in addition, no significant difference was found for phospholipid transfer protein and lipoprotein lipase activities between both patient groups and control subjects . However, hepatic lipase activity was significantly decreased in patients with profile A compared to patients with profile B and control subjects (11 .7 ± 4 vs 18 .2 ± 3 and 22.5 ± 3 tmol/ml/h p < 0.01, respectively) . Furthermore patients with profile A had a significant lower incidence of atherosclerotic lesions than those with profile B . In conclusion, we characterized two distinct HALP profiles that were not related to CETP deficiency . A low incidence of atherosclerotic lesions was associated to high HDL2/HDL3 and LpA-I/LpA-I:A-II ratios suggesting then that HDL2, HDL2b and LpA-I may be the most effective HDL particles for the cardiovascular protection .
4 .P.367
Transcription factor genes controlling high density lipoprotein metabolism
B . Staels . U.325INSERM, Dept. d'Atherosclerose, Institut Pasteur, Lille, France Hypoalphalipoproteinemia is the most common lipoprotein abnormality . Reduced plasma concentrations of HDL-cholesterol and apo A-I, the major HDL apolipoprotein, have been found to be major independent risk factors for coronary artery disease . Plasma HDL concentrations are determined by the interaction of environmental and genetic factors, but the major genetic factors are ill-defined . Our laboratory has been studying the transcriptional control of HDL metabolism and we have focussed on the role of specific transcription factors of the nuclear hormone receptor gene superfamily therein. Nuclear receptors are ligand-activated transcription factors which after activation bind to regulatory regions in target genes thereby modulating their expression level . As such they integrate signals coming from the environment allowing the organism to adapt by changing the expression of specific target genes . We have identified the nuclear receptors PPARct, RORa and Rev-erba as transcriptional regulators of HDL metabolism . These receptors act by influencing the transcription of genes determining HDL levels, such as apo A-I and apo A-II . In addition, absence of their expression profoundly perturbs HDL metabolism . In staggerer mutant mice absence of RORa expression leads to a profound hypoalphalipoproteinemia and an increased susceptibility for atherosclerosis, due to a decreased transcription of the apo A-I gene in the intestine . PPARa, another key-player in the response of HDL to hypolipidemic fibrates and dietary factors, regulates both apo A-I and apo A-II gene expression . Through genetic studies we have now identified a PPARa variant in humans, which may act as a dominant negative form . We speculate that individuals expressing high levels of this variant may be resistant to fibrates . Altogether, these results identify novel genes involved in the control of HDL metabolism . Since these genes code for ligand-activated receptors further research will be aimed at identifying pharmaceutical compounds which may prove of value in the treatment of hypoalphalipoproteinemia and other disorders of lipid and lipoprotein metabolism .
4 .P.368
Sex differences in serum lipoproteins during treatment with carbamazepine
T. Sudhop l , J . Bauer2 , C .E . Elger2 , K. von Bergmann' . 'Department of Clinical Pharmacology : 2 Department of Epileptology, University of Bonn, Germany Epidemiological studies have indicated that patients with seizures treated with antiepileptic drugs have lower mortality from ischaemic heart disease . This has been attributed to the elevation of HDL cholesterol induced by these compounds . However, possible sex differences of antiepileptic drugs have not been examined so far. Therefore, serum lipoproteins were examined in 127 outpatients (56 women and 71 men) treated with carbamazepine (CBZ) and were compared to results obtained in 177 blood donors (67 women and 110 men) matched for age and weight . Patients treated with CBZ had significantly higher levels of total cholesterol compared to controls (women 259 ± 56 mg/dl vs . 197 ± 40 mg/dl, p < 0.001 ; men 239 ± 42 vs. 207 ± 42 mg/dI, p < 0 .001) . Similar results were found for LDL cholesterol (women 160 ± 45 mg/dl vs . 116 ± 41 mg/dl, p < 0 .001 ; men 157 ± 37 mg/dl vs . 134 ±
41 mg/dl, p < 0.001) . Women treated with CBZ showed the highest HDL cholesterol concentrations of all groups (76 ± 25 mg/dl compared to control women 60 f 17 mgldl, p < 0 .001) . This increase was more pronounced than in men (52 f 14 mgldl vs. 45 ± 12 mg/dl, p < 0.001) . Whereas male patients had 7 .5 ± 13 .9 mg/dl (17%) higher HDL cholesterol levels than their male controls, women had two times higher elevations compared to their controls (16.2 ± 25.2 mg/dl [27%] ; p < 0.05) . Conclusion: Patients under treatment with CBZ have increased total, LDL, and HDL cholesterol serum levels . But the anti-atherogenic HDL cholesterol in women is increased almost twice as high as in men . This might be in favor with regard to the development of coronary heart disease in women treated with CBZ . The study was supported by a grant from BMFT (01ECEC9402)
4 .P.369
Decrease in apolipoprotein A-I containing lipoprotein in patients with continuous ambulatory peritoneal dialysis (CAPD)
T. Suzuki, M. Sugasawa, K . Toyama, M . Fukazawa, T. Fujino, T. Murakami. T. Meguro, S . Owada, M. Ishida . St. Mariana University school of Medicine 2-16-1, Sugao, Miyamae-Ku, Kawasaki, Kanagawa, Japan It has been demonstrated that disturbance of lipid metabolism are common in patients with treatment of dialysis . Its characterized by hypertriglyceridemia and decrease of high density lipoprotein (HDL) cholesterol. HDL has reveals that two major apolipoprotein (apo) A-I containing subclasses exist, one that also contains apo A-II (lipoprotein (Lp) A-I :A-II) and one that does not contain apo A-II (LpA-I) . Some studies have demonstrated that serum levels of LpA-I are reduced in patients with atherosclerotic disease . Therefore, we measured serum LpA-I by an immunodiffusion method in patients with treatment of dialysis . Patients were divided into two groups ; hemodialysis (HD): 12 males (M), 1 l females (F), mean age; 62 .3 ± 13 .8 and CAPD : 7 M, 2 F, mean age ; 46 .6 ± 10 .7. There were no significantly difference in serum levels of total cholesterol, triglycerides, HDL-cholesterol, apo A-I and apo A-II between the two groups . However, serum LpA-I levels were significantly decreased in patients in CAPD compared to HD (CAPD ; 44 .3 f 11 .5 vs . HD ; 61 .0 ± 19 .4 mg/dl ; p < 0 .05, respectively) . The levels of LpA-I :A-H did not differ between in two groups. These findings indicate that patients with CAPD have potentially atherosclerotic changes compared to HD because of the significant decrease in serum LpA-I .
.P 4 .370
Cholesterol transport between cells and high density lipoprotein subfractions from obese and lean subjects
D . Sviridov, T. Sasahara, N. Fidge, P. Nestel . Baker Medical Research Institute, Prahran, Australia Since dyslipoproteinemia of obesity is characterized by a changed distribution of high density lipoprotein (HDL) subfractions, we studied the pathway of cholesterol efflux from fibroblasts by testing plasma samples from obese and lean subjects . Plasma samples were incubated with [ 3 H]cholesterol labeled human skin fibroblasts for 1 h to ensure uniform labeling of all HDL subfractions . Supernatants were then transferred to unlabeled cells and the displacement of labeled cholesterol within HDL subfractions by unlabeled cellular cholesterol was analyzed in short-term experiments to define the initial uptake and transfer of cholesterol among HDL particles . Plasma samples of obese subjects were characterized by a lower content of total apolipoprotein A-I (apoA-I) and al-HDL and a lower overall capacity to take up labeled cholesterol, in proportion to the reduced apoA-I concentration . In plasma of lean subjects, pre,82-HDL and at-HDL appeared to be the most active particles in the initial uptake of unlabeled cellular cholesterol, with corresponding transfer of labeled cholesterol to prep 1-HDL, a2-HDL and a3-HDL judged from the decline in [ 3 H]cholesterol from the former and the rise among the latter . By contrast, in plasmas of obese subjects the prep I -HDL appeared to be most active in taking up unlabeled cellular cholesterol and transferring [ 3 H]cholesterol . There were negative correlations between body mass index (BMI) and apoA-I and al-HDL concentrations, and with the apparent increments of cellular cholesterol uptake (area under the curve) within pre$2-HDL and al-HDL, as well as with the overall capacity to promote cholesterol efflux . By contrast, BMI was positively correlated with the apparent increment in cellular cholesterol within prep 1-HDL . While cholesterol efflux was correlated with total plasma apoA-I, there were no such correlations with the concentration of any individual HDL subtraction . We conclude that the pattern of cholesterol transfer between fibroblasts and HDL particles is influenced by body fatness and may be a factor in the abnormal metabolism of HDL in obesity .
11th International Symposium on Atherosclerosis, Paris, October 1997
374
P < 0.01 Profile A n = 22 Profile B n= 7 Controls n = 7
HDL2/HDL3 1 .30 t 0 .28* 0.75 t 0.23 0.65 f 0.23
LpA-I/LpA-I:A-II 1 .01 t 0.2* 0 .69 t 0 .2 0 .71 t 0 .1
HDL2b % 41 .9 t 6* 26 .3 t 5 27 .6 f 4
HDL3a 21 t 4 32 t 3 { 28 f 4
Moreover, the HALP profile A had elevated HDL2b levels whereas profile B had elevated HDL3a levels . CETP mass and activities were higher in patients than in control subjects, in addition, no significant difference was found for phospholipid transfer protein and lipoprotein lipase activities between both patient groups and control subjects . However, hepatic lipase activity was significantly decreased in patients with profile A compared to patients with profile B and control subjects (11 .7 ± 4 vs 18 .2 ± 3 and 22.5 ± 3 tmol/ml/h p < 0.01, respectively) . Furthermore patients with profile A had a significant lower incidence of atherosclerotic lesions than those with profile B . In conclusion, we characterized two distinct HALP profiles that were not related to CETP deficiency . A low incidence of atherosclerotic lesions was associated to high HDL2/HDL3 and LpA-I/LpA-I:A-II ratios suggesting then that HDL2, HDL2b and LpA-I may be the most effective HDL particles for the cardiovascular protection .
4 .P.367
Transcription factor genes controlling high density lipoprotein metabolism
B . Staels . U.325INSERM, Dept. d'Atherosclerose, Institut Pasteur, Lille, France Hypoalphalipoproteinemia is the most common lipoprotein abnormality . Reduced plasma concentrations of HDL-cholesterol and apo A-I, the major HDL apolipoprotein, have been found to be major independent risk factors for coronary artery disease . Plasma HDL concentrations are determined by the interaction of environmental and genetic factors, but the major genetic factors are ill-defined . Our laboratory has been studying the transcriptional control of HDL metabolism and we have focussed on the role of specific transcription factors of the nuclear hormone receptor gene superfamily therein. Nuclear receptors are ligand-activated transcription factors which after activation bind to regulatory regions in target genes thereby modulating their expression level . As such they integrate signals coming from the environment allowing the organism to adapt by changing the expression of specific target genes . We have identified the nuclear receptors PPARct, RORa and Rev-erba as transcriptional regulators of HDL metabolism . These receptors act by influencing the transcription of genes determining HDL levels, such as apo A-I and apo A-II . In addition, absence of their expression profoundly perturbs HDL metabolism . In staggerer mutant mice absence of RORa expression leads to a profound hypoalphalipoproteinemia and an increased susceptibility for atherosclerosis, due to a decreased transcription of the apo A-I gene in the intestine . PPARa, another key-player in the response of HDL to hypolipidemic fibrates and dietary factors, regulates both apo A-I and apo A-II gene expression . Through genetic studies we have now identified a PPARa variant in humans, which may act as a dominant negative form . We speculate that individuals expressing high levels of this variant may be resistant to fibrates . Altogether, these results identify novel genes involved in the control of HDL metabolism . Since these genes code for ligand-activated receptors further research will be aimed at identifying pharmaceutical compounds which may prove of value in the treatment of hypoalphalipoproteinemia and other disorders of lipid and lipoprotein metabolism .
4 .P.368
Sex differences in serum lipoproteins during treatment with carbamazepine
T. Sudhop l , J . Bauer2 , C .E . Elger2 , K. von Bergmann' . 'Department of Clinical Pharmacology : 2 Department of Epileptology, University of Bonn, Germany Epidemiological studies have indicated that patients with seizures treated with antiepileptic drugs have lower mortality from ischaemic heart disease . This has been attributed to the elevation of HDL cholesterol induced by these compounds . However, possible sex differences of antiepileptic drugs have not been examined so far. Therefore, serum lipoproteins were examined in 127 outpatients (56 women and 71 men) treated with carbamazepine (CBZ) and were compared to results obtained in 177 blood donors (67 women and 110 men) matched for age and weight . Patients treated with CBZ had significantly higher levels of total cholesterol compared to controls (women 259 ± 56 mg/dl vs . 197 ± 40 mg/dl, p < 0.001 ; men 239 ± 42 vs. 207 ± 42 mg/dI, p < 0 .001) . Similar results were found for LDL cholesterol (women 160 ± 45 mg/dl vs . 116 ± 41 mg/dl, p < 0 .001 ; men 157 ± 37 mg/dl vs . 134 ±
41 mg/dl, p < 0.001) . Women treated with CBZ showed the highest HDL cholesterol concentrations of all groups (76 ± 25 mg/dl compared to control women 60 f 17 mgldl, p < 0 .001) . This increase was more pronounced than in men (52 f 14 mgldl vs. 45 ± 12 mg/dl, p < 0.001) . Whereas male patients had 7 .5 ± 13 .9 mg/dl (17%) higher HDL cholesterol levels than their male controls, women had two times higher elevations compared to their controls (16.2 ± 25.2 mg/dl [27%] ; p < 0.05) . Conclusion: Patients under treatment with CBZ have increased total, LDL, and HDL cholesterol serum levels . But the anti-atherogenic HDL cholesterol in women is increased almost twice as high as in men . This might be in favor with regard to the development of coronary heart disease in women treated with CBZ . The study was supported by a grant from BMFT (01ECEC9402)
4 .P.369
Decrease in apolipoprotein A-I containing lipoprotein in patients with continuous ambulatory peritoneal dialysis (CAPD)
T. Suzuki, M. Sugasawa, K . Toyama, M . Fukazawa, T. Fujino, T. Murakami. T. Meguro, S . Owada, M. Ishida . St. Mariana University school of Medicine 2-16-1, Sugao, Miyamae-Ku, Kawasaki, Kanagawa, Japan It has been demonstrated that disturbance of lipid metabolism are common in patients with treatment of dialysis . Its characterized by hypertriglyceridemia and decrease of high density lipoprotein (HDL) cholesterol. HDL has reveals that two major apolipoprotein (apo) A-I containing subclasses exist, one that also contains apo A-II (lipoprotein (Lp) A-I :A-II) and one that does not contain apo A-II (LpA-I) . Some studies have demonstrated that serum levels of LpA-I are reduced in patients with atherosclerotic disease . Therefore, we measured serum LpA-I by an immunodiffusion method in patients with treatment of dialysis . Patients were divided into two groups ; hemodialysis (HD): 12 males (M), 1 l females (F), mean age; 62 .3 ± 13 .8 and CAPD : 7 M, 2 F, mean age ; 46 .6 ± 10 .7. There were no significantly difference in serum levels of total cholesterol, triglycerides, HDL-cholesterol, apo A-I and apo A-II between the two groups . However, serum LpA-I levels were significantly decreased in patients in CAPD compared to HD (CAPD ; 44 .3 f 11 .5 vs . HD ; 61 .0 ± 19 .4 mg/dl ; p < 0 .05, respectively) . The levels of LpA-I :A-H did not differ between in two groups. These findings indicate that patients with CAPD have potentially atherosclerotic changes compared to HD because of the significant decrease in serum LpA-I .
.P 4 .370
Cholesterol transport between cells and high density lipoprotein subfractions from obese and lean subjects
D . Sviridov, T. Sasahara, N. Fidge, P. Nestel . Baker Medical Research Institute, Prahran, Australia Since dyslipoproteinemia of obesity is characterized by a changed distribution of high density lipoprotein (HDL) subfractions, we studied the pathway of cholesterol efflux from fibroblasts by testing plasma samples from obese and lean subjects . Plasma samples were incubated with [ 3 H]cholesterol labeled human skin fibroblasts for 1 h to ensure uniform labeling of all HDL subfractions . Supernatants were then transferred to unlabeled cells and the displacement of labeled cholesterol within HDL subfractions by unlabeled cellular cholesterol was analyzed in short-term experiments to define the initial uptake and transfer of cholesterol among HDL particles . Plasma samples of obese subjects were characterized by a lower content of total apolipoprotein A-I (apoA-I) and al-HDL and a lower overall capacity to take up labeled cholesterol, in proportion to the reduced apoA-I concentration . In plasma of lean subjects, pre,82-HDL and at-HDL appeared to be the most active particles in the initial uptake of unlabeled cellular cholesterol, with corresponding transfer of labeled cholesterol to prep 1-HDL, a2-HDL and a3-HDL judged from the decline in [ 3 H]cholesterol from the former and the rise among the latter . By contrast, in plasmas of obese subjects the prep I -HDL appeared to be most active in taking up unlabeled cellular cholesterol and transferring [ 3 H]cholesterol . There were negative correlations between body mass index (BMI) and apoA-I and al-HDL concentrations, and with the apparent increments of cellular cholesterol uptake (area under the curve) within pre$2-HDL and al-HDL, as well as with the overall capacity to promote cholesterol efflux . By contrast, BMI was positively correlated with the apparent increment in cellular cholesterol within prep 1-HDL . While cholesterol efflux was correlated with total plasma apoA-I, there were no such correlations with the concentration of any individual HDL subtraction . We conclude that the pattern of cholesterol transfer between fibroblasts and HDL particles is influenced by body fatness and may be a factor in the abnormal metabolism of HDL in obesity .
11th International Symposium on Atherosclerosis, Paris, October 1997