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PPARγ polymorphisms in patients with familial combined hyperlipidemia (FCHL)
Posters 20. Triglycerides
138 ~-~
TRIGLYCERIDES AS PREDICTOR OF LATE MORTALITY
~-~
IN HEALTHY H Y P E R L I P I D E M I C M E N
POSTPRANDIAL apoB-48 AND apoB-100 CONCENTRATIONS IN PATIENTS W I T H FAMILIAL COMBINED H Y P E R L I P I D E M I A
E.M. Hjerkinn, L. Breivik, L. Sandvik, H. Amesen, I. Hjermann.
Department of Preventive Cardiology, the Division of Cardiology and Research Forum, Ullevaal University Hospital, N-0407 Oslo, Norway
K. Ylitalo, N. Mero-Matikainen, M.-R. Taskinen. Helsinla" University
The aim was to study cholesterol, triglycerides (TG), smoking and blood pressure as potential predictors of 24 years of mortality in hyperlipidemic middle aged men. We studied 104 healthy men aged 4{N49 years with start values of total serum cholesterol > 7.75 mmol/1 and fasting triglycerides > 2.95 mmol/1 within the randomised diet and smoking cessation trial of the Oslo study (n = 1232). 33 subjects died during the 24 years observation period. Only triglycerides and smoking were significantly related to mortality. Non-smokers had 60% reduced mortality compared to smokers (RR = 0.40, p = 0.019) and subjects in the lowest TG quartile (2.95-3.18 mmol/1) had 70% reduction in mortality compared to the remaining subjects (>3.18 mmol/1) (RR = 0.30, p = 0.014). When studied in a Cox regression analysis, only TG was significantly related to mortality, 1.quartile vs 2., 3. and 4 th quartile: RR = 0.24, p = 0.02, after adjusting for age and smoking. For smoking the cox analysis showed a RR = 0.39, p = 0.054.
Patients with familial combined hyperlipidemia (FCHL) are characterised by prolonged postprandial (PP) lipemia, which is an independent risk factor of premature coronary heart disease. By measuring apoB-48 and apoB-100 concentrations in chylomicron (chylo) and VLDL1 particles, we aimed to define the contribution of apoB48 vs. apoB-100 particles to the PP lipemia in FCHL in more detail. Hypertriglyceridemic FCHL patients (4 males, 5 females, mean age 43.3 years, BMI 27.0 kg/m 2) and 9 normolipidemic, age, gender, and BMI matched control subjects (mean age 42.5 yrs, BMI 27.1 kg/m2) underwent a 9-h oral fat load test. Plasma lipid fractions were separated by density gradient ultracentrifugation. Concentrations of apo B-48 and apo B-100 were analysed from chylomicron and VLDL1 fractions using SDS-PAGE. Repeated measures ANOVA was used to analyse the PP responses. ApoB-48 containing particles increased significantly PP in both groups in chylo and VLDL1 fractions (P < 0.01 for each). The increment was higher in FCHL patients than in controls (P < 0.01 for chylo and VLDL1 fractions). ApoB-100 increased significantly in VLDL1 fraction in both groups (P < 0.01), but in chylo fraction there was a significant PP response only in the FCHL group (P = 0.016). There were no differences between the two groups in PP apoB-100 concentrations in chylo or VLDL1 fractions. The PP lipemia was more pronounced in FCHL patients than in controls. Significant differences between the groups could be seen in intestine derived particles that contain apoB-48, which implies that the clearance system of TG-rich particles was saturated in FCHL. Whether this is due to an abnormality in lipolysis, fatty acid uptake in adipose tissue, or remnant clearance by the liver, can not be resolved based on these results.
Triglycertdes
1. quartile
2. quartile
3. quartile
4. quartile
mmol/l n Mortality%
2.95-3.18 26 11.5
3.18-3.8 26 34.6
3.8~..5 26 46.2
4.5-13.8 26 34.6
RR = 0.30, p = 0.014 for 1. quartile vs quartlles 2 + 3 + 4.
This study indicates that high levels of TG (>3.2 mmol) are associated with higher late mortality compared to the range 2.95-3.2 mmol/1 in healthy hyperlipidemic men.
Central Hospital, P.O. Box 340, 00029 HUCH, Finland
~36--~ PPARy P O L Y M O R P H I S M S IN PATIENTS W I T H FAMILIAL COMBINED H Y P E R L I P I D E M I A ( F C H L ) ~-~
EFFECT OF HYPERINSULINEAMIA
AND/OR
H Y P E R G L Y C A E M I A ON THE RATE OF TRIGLYCERIDE CLEARANCE FROM CIRCULATION J. KOV~, V. Fejfarov~i, T. Peli1~nov~i, R. Poledne. Institute for Clinical and
Experimental Medicine, Prague, Czech Republic The rate of triglyceride clearance from circulation is one of the key factors determining triglyceridaemia, especially in the postprandial state. It is likely to be strongly affected by the concurrent increase in insulinaemia and glycaemia that are also typical features of the postprandial phase. To evaluate the effect of acutely induced hyperinsulinaemia and hyperglycaemia on the rate of triglyceride removal from circulation in vivo, we measured the k2 rate constant for clearance of intravenously administered fat emulsion (Intralipid, 0.1 g of faffkg) after the following interventions lasting 4 hours: a) control infusion of saline [C], b) euglycaemic hyperinsulinaemic clamp (hyperinsulinaemia [HI]), c) hyperglycaemic clamp with somatostatin infusion (hyperglycaemia [HG]), d) hyperglycaemic clamp (hyperinsulinaemia and hyperglycemia [HGHI]). The blood glucose levels were maintained at 17 mmol/L during both hyperglycaemic clamps. The study was carried out in 10 healthy young men (age: 274-6 years; BMI: 24.35:3.0 kg/m2; insulin: 74-3 mlU/L; cholesterol: 4.14-0.4 mmol/L; TG: 1.04-0.3 mmol/L). While both hyperinsulinaemia and hyperglycaemia alone did not affect the rate of Intralipid clearance; when combined, they did reduce the k2 rate constant to a half.
k2 (%/rain)
c
HI
HG
HGHI
6.26** ±2.18
6.29** ±3.65
5.51** -I-2.16
3.36 ±1.26
K. Ylitalo 1, J. PihlajamSki, J. Auwerx, M.-R. Task±hen, M. Laakso.
I Helsinki University Central Hospital, P.O. Box 340, 00029 HUCH, Finland The aim of the study was to evaluate if the Pro12Ala or C161T polymorphism of PPARy gene has an effect on serum lipids or other related metabolic parameters in Finnish patients with FCHL. The two variants of PPARy gene were studied in 38 FCHL patients from 20 families. Gene variants were detected with SSCP. Subjects with different genotypes were compared for serum lipids, and other related variables The characteristics of the subjects divided by Pro 12Ala polymorphism are shown in the Table. There were not even near significant differences in the above mentioned variables when subjects with at least one T-allele (n = 8) were compared with those who had the genotype C161C (n = 30). Pro/Pro (n=27,10 M/17F) Pro/Ala + Ala/Ala P-value (n=l 1, 5 M/6 F) Age (years) TC (mmol/1) TG (mmol/l) HDL-C(retool/l) Apo B (mg/dl) Fastinginsulin(mU/1) BMI (kg/m2)
38.9±12.0 6.27±0.99 1.955-0.95 1.355-0.57 110±25 10.1±4.7 26.8±3.7
47.15-10.4 6.695-1.01 1.365-0.61 h745-0.63 t 124-20 6.85-3.3 29.1±5.5
0.055 0.25 0.051
0.07 0.81 0.054
0.21
A trend toward lower serum TG and insulin, and higher HDL-C in FCHL patients who carry at least one Ala-allele is seen in this small FCHL cohort. In this cohort Ala-allele was associated with higher BMI. It is likely that PPARy plays a modifying role in FCHL. Whether this results primarily from its effects on energy, lipid, or glucose homeostasis, requires further studies.
• * - p < 0.01 vs HGHI Although the mechanism operating beyond the suppresion of triglyceride clearance under combined hyperinsulinaemia and hyperglycaemia is not clear yet, it could play a certain role in disturbances of triglyceride-rich lipoprotein metabolism during postprandial lipaemia in insulin-resistant and type 2 diabetic subjects. Supported by grant No. NB 6368-3 from IGA MH CR.
72nd EAS Congress
138 ~-~
TRIGLYCERIDES AS PREDICTOR OF LATE MORTALITY
~-~
IN HEALTHY H Y P E R L I P I D E M I C M E N
POSTPRANDIAL apoB-48 AND apoB-100 CONCENTRATIONS IN PATIENTS W I T H FAMILIAL COMBINED H Y P E R L I P I D E M I A
E.M. Hjerkinn, L. Breivik, L. Sandvik, H. Amesen, I. Hjermann.
Department of Preventive Cardiology, the Division of Cardiology and Research Forum, Ullevaal University Hospital, N-0407 Oslo, Norway
K. Ylitalo, N. Mero-Matikainen, M.-R. Taskinen. Helsinla" University
The aim was to study cholesterol, triglycerides (TG), smoking and blood pressure as potential predictors of 24 years of mortality in hyperlipidemic middle aged men. We studied 104 healthy men aged 4{N49 years with start values of total serum cholesterol > 7.75 mmol/1 and fasting triglycerides > 2.95 mmol/1 within the randomised diet and smoking cessation trial of the Oslo study (n = 1232). 33 subjects died during the 24 years observation period. Only triglycerides and smoking were significantly related to mortality. Non-smokers had 60% reduced mortality compared to smokers (RR = 0.40, p = 0.019) and subjects in the lowest TG quartile (2.95-3.18 mmol/1) had 70% reduction in mortality compared to the remaining subjects (>3.18 mmol/1) (RR = 0.30, p = 0.014). When studied in a Cox regression analysis, only TG was significantly related to mortality, 1.quartile vs 2., 3. and 4 th quartile: RR = 0.24, p = 0.02, after adjusting for age and smoking. For smoking the cox analysis showed a RR = 0.39, p = 0.054.
Patients with familial combined hyperlipidemia (FCHL) are characterised by prolonged postprandial (PP) lipemia, which is an independent risk factor of premature coronary heart disease. By measuring apoB-48 and apoB-100 concentrations in chylomicron (chylo) and VLDL1 particles, we aimed to define the contribution of apoB48 vs. apoB-100 particles to the PP lipemia in FCHL in more detail. Hypertriglyceridemic FCHL patients (4 males, 5 females, mean age 43.3 years, BMI 27.0 kg/m 2) and 9 normolipidemic, age, gender, and BMI matched control subjects (mean age 42.5 yrs, BMI 27.1 kg/m2) underwent a 9-h oral fat load test. Plasma lipid fractions were separated by density gradient ultracentrifugation. Concentrations of apo B-48 and apo B-100 were analysed from chylomicron and VLDL1 fractions using SDS-PAGE. Repeated measures ANOVA was used to analyse the PP responses. ApoB-48 containing particles increased significantly PP in both groups in chylo and VLDL1 fractions (P < 0.01 for each). The increment was higher in FCHL patients than in controls (P < 0.01 for chylo and VLDL1 fractions). ApoB-100 increased significantly in VLDL1 fraction in both groups (P < 0.01), but in chylo fraction there was a significant PP response only in the FCHL group (P = 0.016). There were no differences between the two groups in PP apoB-100 concentrations in chylo or VLDL1 fractions. The PP lipemia was more pronounced in FCHL patients than in controls. Significant differences between the groups could be seen in intestine derived particles that contain apoB-48, which implies that the clearance system of TG-rich particles was saturated in FCHL. Whether this is due to an abnormality in lipolysis, fatty acid uptake in adipose tissue, or remnant clearance by the liver, can not be resolved based on these results.
Triglycertdes
1. quartile
2. quartile
3. quartile
4. quartile
mmol/l n Mortality%
2.95-3.18 26 11.5
3.18-3.8 26 34.6
3.8~..5 26 46.2
4.5-13.8 26 34.6
RR = 0.30, p = 0.014 for 1. quartile vs quartlles 2 + 3 + 4.
This study indicates that high levels of TG (>3.2 mmol) are associated with higher late mortality compared to the range 2.95-3.2 mmol/1 in healthy hyperlipidemic men.
Central Hospital, P.O. Box 340, 00029 HUCH, Finland
~36--~ PPARy P O L Y M O R P H I S M S IN PATIENTS W I T H FAMILIAL COMBINED H Y P E R L I P I D E M I A ( F C H L ) ~-~
EFFECT OF HYPERINSULINEAMIA
AND/OR
H Y P E R G L Y C A E M I A ON THE RATE OF TRIGLYCERIDE CLEARANCE FROM CIRCULATION J. KOV~, V. Fejfarov~i, T. Peli1~nov~i, R. Poledne. Institute for Clinical and
Experimental Medicine, Prague, Czech Republic The rate of triglyceride clearance from circulation is one of the key factors determining triglyceridaemia, especially in the postprandial state. It is likely to be strongly affected by the concurrent increase in insulinaemia and glycaemia that are also typical features of the postprandial phase. To evaluate the effect of acutely induced hyperinsulinaemia and hyperglycaemia on the rate of triglyceride removal from circulation in vivo, we measured the k2 rate constant for clearance of intravenously administered fat emulsion (Intralipid, 0.1 g of faffkg) after the following interventions lasting 4 hours: a) control infusion of saline [C], b) euglycaemic hyperinsulinaemic clamp (hyperinsulinaemia [HI]), c) hyperglycaemic clamp with somatostatin infusion (hyperglycaemia [HG]), d) hyperglycaemic clamp (hyperinsulinaemia and hyperglycemia [HGHI]). The blood glucose levels were maintained at 17 mmol/L during both hyperglycaemic clamps. The study was carried out in 10 healthy young men (age: 274-6 years; BMI: 24.35:3.0 kg/m2; insulin: 74-3 mlU/L; cholesterol: 4.14-0.4 mmol/L; TG: 1.04-0.3 mmol/L). While both hyperinsulinaemia and hyperglycaemia alone did not affect the rate of Intralipid clearance; when combined, they did reduce the k2 rate constant to a half.
k2 (%/rain)
c
HI
HG
HGHI
6.26** ±2.18
6.29** ±3.65
5.51** -I-2.16
3.36 ±1.26
K. Ylitalo 1, J. PihlajamSki, J. Auwerx, M.-R. Task±hen, M. Laakso.
I Helsinki University Central Hospital, P.O. Box 340, 00029 HUCH, Finland The aim of the study was to evaluate if the Pro12Ala or C161T polymorphism of PPARy gene has an effect on serum lipids or other related metabolic parameters in Finnish patients with FCHL. The two variants of PPARy gene were studied in 38 FCHL patients from 20 families. Gene variants were detected with SSCP. Subjects with different genotypes were compared for serum lipids, and other related variables The characteristics of the subjects divided by Pro 12Ala polymorphism are shown in the Table. There were not even near significant differences in the above mentioned variables when subjects with at least one T-allele (n = 8) were compared with those who had the genotype C161C (n = 30). Pro/Pro (n=27,10 M/17F) Pro/Ala + Ala/Ala P-value (n=l 1, 5 M/6 F) Age (years) TC (mmol/1) TG (mmol/l) HDL-C(retool/l) Apo B (mg/dl) Fastinginsulin(mU/1) BMI (kg/m2)
38.9±12.0 6.27±0.99 1.955-0.95 1.355-0.57 110±25 10.1±4.7 26.8±3.7
47.15-10.4 6.695-1.01 1.365-0.61 h745-0.63 t 124-20 6.85-3.3 29.1±5.5
0.055 0.25 0.051
0.07 0.81 0.054
0.21
A trend toward lower serum TG and insulin, and higher HDL-C in FCHL patients who carry at least one Ala-allele is seen in this small FCHL cohort. In this cohort Ala-allele was associated with higher BMI. It is likely that PPARy plays a modifying role in FCHL. Whether this results primarily from its effects on energy, lipid, or glucose homeostasis, requires further studies.
• * - p < 0.01 vs HGHI Although the mechanism operating beyond the suppresion of triglyceride clearance under combined hyperinsulinaemia and hyperglycaemia is not clear yet, it could play a certain role in disturbances of triglyceride-rich lipoprotein metabolism during postprandial lipaemia in insulin-resistant and type 2 diabetic subjects. Supported by grant No. NB 6368-3 from IGA MH CR.
72nd EAS Congress