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Effects of various fibrates on serum alkaline phosphatase activity
112
Ganotakis
removal of oxysterols in neurodegenerative disease and transport of lipidsoluble vitamins. In plasma and interstitial fluid, phospholipid transfer protein (PLTP) induces HDL conversion, stimulates cholesterol efflux and transfers vitamin E between lipoproteins and cells. Therefore, we were curious as to whether PLTP also participates in lipid metabolism in CSE To characterize the tissue specific expression of PLTP in the CNS of rabbits, which - like humans - express both lipid transfer proteins, PLTP and cholesterylester transfer protein (CETP), we analyzed PLTP mRNA and protein synthesis with several techniques. In a first step, we determined the overall PLTP mRNA content of whole-brain-samples in comparison to eight other rabbit tissues by Northern Blotting. Interestingly only pancreas and adipose tissue yielded higher PLTP mRNA expression than brain. In situ hybridizations on frontal and paramedian rabbit brain sections using radiolabeled oligonucleotide probes revealed pronounced staining in the periventricular area, especially, in the choroid plexus and the ependyma the structures responsible for the secretion of cerebrospinal fluid (CSF). In addition, PLTP expression was clearly detectable in corpus striatum and cortical grey matter. Phospholipid transfer activity in rabbit CSF averaged 23±3% of rabbit plasma and we were able to detect PLTP in rabbit CSF by Western blotting using a polyclonal antibody generated in chicken. In order to exclude the possibility that CSF-PLTP activity derives from plasma, we analysed tissue distribution and CSF activity of the structurally related cholesterylester transfer protein (CETP). CETP mRNA was not detectable in rabbit brain, and CETP activity, which was substantial in rabbit plasma, was not present in rabbit CSF (0±0% of plasma activity). In conclusion, this is the first detailed report of lipid transfer protein expression in the CNS. We demonstrate that rabbit brain synthesizes and secretes high levels of PLTP, in a process that is fairly specific for choroid plexus and ependyma, the neuroanatomic structures responsible for the production ofCSE A role of PLTP in the central nervous system could involve some of its actions previously established in vitro like distributing vitamin E, remodeling cerebrospinal fluid HDL and proteolysis of apolipoproteins and be physiologically relevant for neurodegenerative disorders such as Alzheimer' s disease. ~]
EFFECTS OF VARIOUS FIBRATES ON SERUM ALKALINE PHOSPHATASE ACTIVITY
E. Ganotakis 1, V. Tsimihodimos2, E. Rizos 2, H. Milionis 2, V. Athyros2, E. Bairaktari 3, C. Seferiades 3, M. Elisaf2. 1Department of Internal
Medicine, Medical School, University of Crete, Heraklion," 2Department of Internal Medicine, Medical School, University of loannina," 3Laboratory of Biochemistry, School of Chemistry, University of loannina, Greece A number of studies have found that fibrates can significantly decrease serum alkaline phosphatase (AL) activity, though neither the underlying mechanisms nor the significance of this effect are clear-cut. However, there are no comparative data on the influence of the various drugs of this class on AL activity in patients with hyperlipidemia. Thus, we retrospectively studied the cards of our patients treated with fibrates. All fibrates significantly reduced serum AL activity [bezafibrate by 23%, fenofibrate by 14%, ciprofibrate by 17%, and gemfibrozil by 4%]. No significant changes in serum transaminases and y-glutamyl transpeptidase (yGT) activity were noticed in the four groups studied, though there was a trend towards a yGT decrease. The changes induced by ciprofibrate, bezafibrate and fenofibrate were significantly greater to those noticed after gemfibrozil (p<0.0001 for all comparisons). Even though the bezafibrate-induced decrease in serum ALP activity was higher than that observed after ciprofibrate and fenofibrate, these differences were not significant (by analysis of covariance taking into account the baseline values as a covariate). Thus, our study reconfirms the ability of fibrates to reduce ALP activity. However, it also shows for the first time that the effect of gemfibrozil on ALP activity is considerably weaker compared to the other fibric acid derivatives. It should be stated that this decrease in serum ALP activity can be as a reliable marker of patients compliance. We conclude that fibrates, can significantly decrease serum ALP activity. ~-~
SERUM LIPID ABNORMALITIES IN PATIENTS W I T H ACUTE MYOCARDIAL INFARCTION
D. Papakonstantinou 1, E. Alexopoulos 1, G. Vrentzos2, J.A. Papadakis 2, E. Ganotakis 2. JDepartment of Cardiology, Rodos General Hospital,
Rodos," 2Department of Internal Medicine, University Hospital of Crete, Heraklion, Greece Objectives: Serum lipids abnormalities significantly contribute on the risk of coronary heart disease (CHD). While the relationship between lowdensity lipoprotein cholesterol (LDL-C) levels and CHD is well documented
in major epidemiological studies, low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides (TG) are included in the lipid abnormalities that go beyond elevated LDL-C. The aim of this study was to evaluate the lipid abnormalities in patients admitted to the coronary unit with acute myocardial infarction at Rodos General Hospital in 12 months period. In this part of Greece life style habits have changed spectacularly the last decades. Material and Methods: Medical records of 181 patients were retrospectively studied. Eighty were excluded (50 because of their origin and 30 because of missing data). Serum lipids were performed within 8 hours from the onset of acute symptoms. Results: 61 males out of 84 (73%) were non-diabetics, while in 17 women, diabetes was found in 13 (66.4%). Our population lipid values (expressed as mean±SD) were: TC-253±56mg/dl, HDL-C-34±9mg/dl, LDL-C-186±53mg/dl, TG-164±76mg/dl and TC/HDL-C ratio-7.8±2. HDL-C<40mg/dl was found in 77%, LDL-C>160mg/dl in 37% and TG>150mg/dl in 51% of non-diabetics, and finally 22% of them had HDL-C<40mg/dl, LDL-C>130mg/dl and TG>150mg/dl. Conclusions: The cardinal lipid abnormality in non diabetic patients with AMI in this particular part of Greece is low HDL-C levels. Further effort in recognizing this abnormality and aggressive intervention in population is needed.
~ - - ~ INFLUENCE OF BIRTH W E I G H T ON THE APO E GENETIC DETERMINANTS OF PLASMA LIPID LEVELS IN CHILDREN C. Garces 1, M. Benavente 1, H. Ortega2, E. Viturro 1, B. Cano 1, M.A. Lasuncion2, E Rodriguez Artalejo 1, M. De Oya 1. IFundacion
Jimenez Diaz," 2Hospital Ramon y Cajal, Madrid, Spain To evaluate the influence of birth weight on apo E genetic determinants of plasma lipid levels in pre-puberal children we studied 933 healthy children (491 males and 442 females) between 6 and 8 years old, with an average age of 6.7 years whose weight was recorded at birth. Plasma lipid and apolipoprotein concentrations and apo E genotypes were determined. We observed a greater effect of the apo E polymorphism on TC, LDL-C and specially apo B levels in children with birth weight in the low percentile compared with those with birth weights in higher tertiles. Taking the epsilon3 allele homozygosity as reference, in boys with birth weights in the low tertile the overall lowering effect of the epsilon2 allele on TC, LDL-C and apo B was greater (10.5% (p<0.01), 20.2% (p<0.01) and 18.8% (p<0.01), respectively) than in those in the highest tertile, (5.6% on TC.3% on LDL-C and 12.6% (p<0.01) on apo B). A similar trend in this effect between tertiles of birth weight was also observed in girls. Our findings demonstrate the influence of birth weight on the effect of apo E genotype contribution to plasma lipid levels, being more important in children in the low tertile of birth weight. Taking into account the prevalence of apo E polymorphism, and that appears to be the main genetic factor affecting plasma lipids, the interaction of apo E genotype and birth weight could be an important determinant of TC, LDL-C and apo B levels, and, as a consequence, of athero sclero sis. Study sponsored by Fundacion Ramon Areces.
•1--•
APOE GENOTYPE AS A RISK FACTOR OF MYOCARDIAL INFARCTION IN YOUNG PEOPLE
C. Garces, M. Benavente, E. Viturro, B. Cano, J. Romero, E. Martin, J. Farre, M. De Oya. Fundacion Jimenez Diaz, Madrid, Spain Background: Apo E is a key regulator of plasma lipid levels. Six common genotypes of apo E typically occur, corresponding to the combination of the epsilon2, epsilon3 and epsilon4 alleles. Epsilon3epsilon4 genotype has been associated with increased plasma lipid levels and risk of cardiovascular disease. We have evaluated the role of this potential risk factor in the incidence of myocardial infarction (MI) in our population. Methods: Besides analysing other classical risk factors, we have determined ApoE genotypes by PCR amplification and restriction enzyme analysis in 112 survivors of MI, admitted at the Coronary Care Unit at our hospital, classified in different groups of age. Results: We have found a significantly higher frequency of smokers and carriers of the epsilon3epsilon4 genotype in the group of youngest patients with MI compared with the oldest (table 1).
73rd EAS Congress
Ganotakis
removal of oxysterols in neurodegenerative disease and transport of lipidsoluble vitamins. In plasma and interstitial fluid, phospholipid transfer protein (PLTP) induces HDL conversion, stimulates cholesterol efflux and transfers vitamin E between lipoproteins and cells. Therefore, we were curious as to whether PLTP also participates in lipid metabolism in CSE To characterize the tissue specific expression of PLTP in the CNS of rabbits, which - like humans - express both lipid transfer proteins, PLTP and cholesterylester transfer protein (CETP), we analyzed PLTP mRNA and protein synthesis with several techniques. In a first step, we determined the overall PLTP mRNA content of whole-brain-samples in comparison to eight other rabbit tissues by Northern Blotting. Interestingly only pancreas and adipose tissue yielded higher PLTP mRNA expression than brain. In situ hybridizations on frontal and paramedian rabbit brain sections using radiolabeled oligonucleotide probes revealed pronounced staining in the periventricular area, especially, in the choroid plexus and the ependyma the structures responsible for the secretion of cerebrospinal fluid (CSF). In addition, PLTP expression was clearly detectable in corpus striatum and cortical grey matter. Phospholipid transfer activity in rabbit CSF averaged 23±3% of rabbit plasma and we were able to detect PLTP in rabbit CSF by Western blotting using a polyclonal antibody generated in chicken. In order to exclude the possibility that CSF-PLTP activity derives from plasma, we analysed tissue distribution and CSF activity of the structurally related cholesterylester transfer protein (CETP). CETP mRNA was not detectable in rabbit brain, and CETP activity, which was substantial in rabbit plasma, was not present in rabbit CSF (0±0% of plasma activity). In conclusion, this is the first detailed report of lipid transfer protein expression in the CNS. We demonstrate that rabbit brain synthesizes and secretes high levels of PLTP, in a process that is fairly specific for choroid plexus and ependyma, the neuroanatomic structures responsible for the production ofCSE A role of PLTP in the central nervous system could involve some of its actions previously established in vitro like distributing vitamin E, remodeling cerebrospinal fluid HDL and proteolysis of apolipoproteins and be physiologically relevant for neurodegenerative disorders such as Alzheimer' s disease. ~]
EFFECTS OF VARIOUS FIBRATES ON SERUM ALKALINE PHOSPHATASE ACTIVITY
E. Ganotakis 1, V. Tsimihodimos2, E. Rizos 2, H. Milionis 2, V. Athyros2, E. Bairaktari 3, C. Seferiades 3, M. Elisaf2. 1Department of Internal
Medicine, Medical School, University of Crete, Heraklion," 2Department of Internal Medicine, Medical School, University of loannina," 3Laboratory of Biochemistry, School of Chemistry, University of loannina, Greece A number of studies have found that fibrates can significantly decrease serum alkaline phosphatase (AL) activity, though neither the underlying mechanisms nor the significance of this effect are clear-cut. However, there are no comparative data on the influence of the various drugs of this class on AL activity in patients with hyperlipidemia. Thus, we retrospectively studied the cards of our patients treated with fibrates. All fibrates significantly reduced serum AL activity [bezafibrate by 23%, fenofibrate by 14%, ciprofibrate by 17%, and gemfibrozil by 4%]. No significant changes in serum transaminases and y-glutamyl transpeptidase (yGT) activity were noticed in the four groups studied, though there was a trend towards a yGT decrease. The changes induced by ciprofibrate, bezafibrate and fenofibrate were significantly greater to those noticed after gemfibrozil (p<0.0001 for all comparisons). Even though the bezafibrate-induced decrease in serum ALP activity was higher than that observed after ciprofibrate and fenofibrate, these differences were not significant (by analysis of covariance taking into account the baseline values as a covariate). Thus, our study reconfirms the ability of fibrates to reduce ALP activity. However, it also shows for the first time that the effect of gemfibrozil on ALP activity is considerably weaker compared to the other fibric acid derivatives. It should be stated that this decrease in serum ALP activity can be as a reliable marker of patients compliance. We conclude that fibrates, can significantly decrease serum ALP activity. ~-~
SERUM LIPID ABNORMALITIES IN PATIENTS W I T H ACUTE MYOCARDIAL INFARCTION
D. Papakonstantinou 1, E. Alexopoulos 1, G. Vrentzos2, J.A. Papadakis 2, E. Ganotakis 2. JDepartment of Cardiology, Rodos General Hospital,
Rodos," 2Department of Internal Medicine, University Hospital of Crete, Heraklion, Greece Objectives: Serum lipids abnormalities significantly contribute on the risk of coronary heart disease (CHD). While the relationship between lowdensity lipoprotein cholesterol (LDL-C) levels and CHD is well documented
in major epidemiological studies, low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides (TG) are included in the lipid abnormalities that go beyond elevated LDL-C. The aim of this study was to evaluate the lipid abnormalities in patients admitted to the coronary unit with acute myocardial infarction at Rodos General Hospital in 12 months period. In this part of Greece life style habits have changed spectacularly the last decades. Material and Methods: Medical records of 181 patients were retrospectively studied. Eighty were excluded (50 because of their origin and 30 because of missing data). Serum lipids were performed within 8 hours from the onset of acute symptoms. Results: 61 males out of 84 (73%) were non-diabetics, while in 17 women, diabetes was found in 13 (66.4%). Our population lipid values (expressed as mean±SD) were: TC-253±56mg/dl, HDL-C-34±9mg/dl, LDL-C-186±53mg/dl, TG-164±76mg/dl and TC/HDL-C ratio-7.8±2. HDL-C<40mg/dl was found in 77%, LDL-C>160mg/dl in 37% and TG>150mg/dl in 51% of non-diabetics, and finally 22% of them had HDL-C<40mg/dl, LDL-C>130mg/dl and TG>150mg/dl. Conclusions: The cardinal lipid abnormality in non diabetic patients with AMI in this particular part of Greece is low HDL-C levels. Further effort in recognizing this abnormality and aggressive intervention in population is needed.
~ - - ~ INFLUENCE OF BIRTH W E I G H T ON THE APO E GENETIC DETERMINANTS OF PLASMA LIPID LEVELS IN CHILDREN C. Garces 1, M. Benavente 1, H. Ortega2, E. Viturro 1, B. Cano 1, M.A. Lasuncion2, E Rodriguez Artalejo 1, M. De Oya 1. IFundacion
Jimenez Diaz," 2Hospital Ramon y Cajal, Madrid, Spain To evaluate the influence of birth weight on apo E genetic determinants of plasma lipid levels in pre-puberal children we studied 933 healthy children (491 males and 442 females) between 6 and 8 years old, with an average age of 6.7 years whose weight was recorded at birth. Plasma lipid and apolipoprotein concentrations and apo E genotypes were determined. We observed a greater effect of the apo E polymorphism on TC, LDL-C and specially apo B levels in children with birth weight in the low percentile compared with those with birth weights in higher tertiles. Taking the epsilon3 allele homozygosity as reference, in boys with birth weights in the low tertile the overall lowering effect of the epsilon2 allele on TC, LDL-C and apo B was greater (10.5% (p<0.01), 20.2% (p<0.01) and 18.8% (p<0.01), respectively) than in those in the highest tertile, (5.6% on TC.3% on LDL-C and 12.6% (p<0.01) on apo B). A similar trend in this effect between tertiles of birth weight was also observed in girls. Our findings demonstrate the influence of birth weight on the effect of apo E genotype contribution to plasma lipid levels, being more important in children in the low tertile of birth weight. Taking into account the prevalence of apo E polymorphism, and that appears to be the main genetic factor affecting plasma lipids, the interaction of apo E genotype and birth weight could be an important determinant of TC, LDL-C and apo B levels, and, as a consequence, of athero sclero sis. Study sponsored by Fundacion Ramon Areces.
•1--•
APOE GENOTYPE AS A RISK FACTOR OF MYOCARDIAL INFARCTION IN YOUNG PEOPLE
C. Garces, M. Benavente, E. Viturro, B. Cano, J. Romero, E. Martin, J. Farre, M. De Oya. Fundacion Jimenez Diaz, Madrid, Spain Background: Apo E is a key regulator of plasma lipid levels. Six common genotypes of apo E typically occur, corresponding to the combination of the epsilon2, epsilon3 and epsilon4 alleles. Epsilon3epsilon4 genotype has been associated with increased plasma lipid levels and risk of cardiovascular disease. We have evaluated the role of this potential risk factor in the incidence of myocardial infarction (MI) in our population. Methods: Besides analysing other classical risk factors, we have determined ApoE genotypes by PCR amplification and restriction enzyme analysis in 112 survivors of MI, admitted at the Coronary Care Unit at our hospital, classified in different groups of age. Results: We have found a significantly higher frequency of smokers and carriers of the epsilon3epsilon4 genotype in the group of youngest patients with MI compared with the oldest (table 1).
73rd EAS Congress