S. Meijssen

Diurnal triglyceride profiles: a novel approach to study triglyceride changes

Fasting plasma triglycerides (TG) show a high intra-individual variability, and therefore, repeated measurements and alternative methodology are necessary when studying TG metabolism. In search for novel approaches to study TG changes, we evaluated the feasibility of determining ambulatory capillary TG. In addition, well-known characteristics (e.g. gender differences) of TG metabolism in healthy subjects were determined. In 18 subjects with a wide range of fasting plasma TG, the results of standardised oral fat loading tests (50 g m(-2)) were compared to their diurnal capillary TG profiles, measured on 3 different days, six times each day in an out-patient clinic setting. The diurnal TG-profile was calculated as area under the capillary TG curve (TGc-AUC) and as incremental area (dTGc-AUC). Clearance of plasma TG after the acute oral fat load correlated well with the diurnal TGc-AUC (r=0.77; P<0.01). In addition, hypertriglyceridemic subjects (plasma TG >2.0 mmol l(-1)) had a higher diurnal triglyceridemia (49.83+/-15.37 h mmol l(-1)) as well as a higher response of plasma TG to the oral fat load (42.10+/-15.37 h mmol l(-1)), than the subjects with normal fasting plasma TG (29.83+/-11.75 h mmol l(-1) (P<0.05) and 20.75+/-5.89 h mmol l(-1) (P<0.01), respectively). In an observational study, 106 volunteers (54 females and 52 males) measured capillary triglycerides. Food intake was recorded and fasting blood was drawn once at the start of the study. Body composition was assessed by anthropometric parameters and body-impedance. Repeated measurements of diurnal triglyceridemia tended to be less variable than fasting capillary triglycerides (mean coefficients of variation 15.1% (range: 0.60-45.9%) and 24.9% (range: 1.44-72.7%), respectively; P=0.09) for the whole group and in males (18.6% (0.60-45.9%) and 24.0% (1.4-58.2%), respectively; P=0.07). The mean diurnal TGc-AUC and dTGc-AUC were lower in females (16.50+/-4.85 and 1.82+/-3.46 h mmol l(-1), respectively) than in males (23.44+/-6.50 and 6.93+/-4.67 h mmol l(-1); P<0.001 for each). The total daily energy intake was lower in females (8911+/-1905 kJ) than in males (11042+/-2604 kJ, P<0.001) because of a lower intake of all nutrients. In females, estrogen status determined significantly the capillary TG profiles. Stepwise multiple regression analysis for females and males, with TGc-AUC as the dependent variable, showed that the best predictors were fasting capillary TG, gender, systolic blood pressure and mean daily energy intake, explaining 72% of the variation. Incremental triglyceridemia was best described by gender, mean daily protein intake and systolic blood pressure, explaining 42% of the variation. Diurnal capillary TG profiles may be used to estimate the total daily load of potential atherogenic particles to which individuals are subjected during the day without the need for metabolic ward studies.

Delayed and Exaggerated Postprandial Complement Component 3 Response in Familial Combined Hyperlipidemia

Very low density lipoprotein overproduction is the major metabolic characteristic in familial combined hyperlipidemia (FCHL). Peripheral handling of free fatty acids (FFAs) in vitro may be impaired in FCHL by decreased action of acylation-stimulating protein (ASP), which is identical to the immunologically inactive complement component 3a (C3adesArg). Because decreased FFA uptake by impaired complement component 3 (C3) response (as the precursor for ASP) may result in enhanced FFA flux to the liver in FCHL, we have evaluated postprandial C3 changes in vivo in FCHL patients. Accordingly, 10 untreated FCHL patients and 10 matched control subjects underwent an oral fat loading test. Fasting plasma C3 and ASP levels were higher in FCHL patients (1.33±0.09 g/L and 70.53±4.37 mmol/L, respectively) than in control subjects (0.91±0.03 g/L and 43.21±8.96 mmol/L, respectively;P =0.01 and P <0.05). In control subjects, C3 concentrations increased significantly after 4 hours (to 1.03±0.04 g/L). In FCHL, plasma C3 was unchanged after 4 hours. The earliest postprandial C3 rise in FCHL patients occurred after 8 hours (1.64±0.12 g/L). The maximal apolipoprotein B-48 concentration was reached after 6 hours in FCHL patients and control subjects. Postprandial FFA and hydroxybutyric acid (as a marker of hepatic FFA oxidation) were significantly higher in FCHL patients than in control subjects, and the early postprandial C3 rise was negatively correlated with the postprandial FFA and hydroxybutyric acid concentrations. The present data suggest an impaired postprandial plasma C3 response in FCHL patients, most likely as a result of a delayed response by C3, as the precursor for the biologically active ASP, acting on FFA metabolism. Therefore, an impaired postprandial C3 response may be associated with impaired peripheral postprandial FFA uptake and, consequently, lead to increased hepatic FFA flux and very low density lipoprotein overproduction.

Intra-individual variations of fasting plasma lipids, apolipoproteins and postprandial lipemia in familial combined hyperlipidemia compared to controls

BACKGROUND The intra-individual variability of plasma lipids and apolipoproteins has not been studied systematically in familial combined hyperlipidemia (FCHL). METHODS Intra-individual changes in fasting plasma lipids and apolipoproteins B and AI were determined in 18 untreated FCHL subjects and 16 unrelated, normolipidemic subjects. Participants were matched for gender, age and body mass index. The mean follow-up period of fasting plasma lipids was 48.91 +/- 35.46 (mean +/- S.D.) days. Postprandial lipemia was determined on 3 different days in 1 week in 90 healthy controls and 17 untreated FCHL subjects by the area under the diurnal capillary triglyceride curve (TGc-AUC). RESULTS The coefficients of variation (CVs) for fasting plasma TG were similar between FCHL (23.2 +/- 10.2%) and controls (20.4 +/- 8.2%). The CVs for HDL-C, apo B and apo AI were the lowest of all fasting plasma measurements in both groups and there was no significant difference between FCHL (12.8 +/- 8.2%, 13.2 +/- 15.8% and 6.4 +/- 5.2%, respectively) and controls (11.4 +/- 4.3%, 11.3 +/- 10.6% and 7.8 +/- 4.6%, respectively). The CVs for postprandial lipemia were not different between FCHL (15.9 +/- 11.3%) and controls (15.1 +/- 11.0%), and were significantly lower than the CV of fasting capillary TG (TGc) in the same period (36.3 +/- 24.7% and 24.9 +/- 17.2%, respectively). CONCLUSIONS Our study does not provide evidence for short-term major changes in fasting or postprandial lipemia or apolipoproteins in FCHL when systematically compared to healthy controls.

Gender Differences in Postprandial Ketone Bodies in Normolipidemic Subjects and in Untreated Patients With Familial Combined Hyperlipidemia

Objective—An increased hepatic flow of free fatty acids (FFAs) is associated with impaired peripheral FFA trapping by malfunctioning of the complement component 3 (C3)/acylation-stimulating protein system and overproduction of VLDL in familial combined hyperlipidemia (FCHL). Postprandial ketone bodies reflect FFA oxidation in the liver, but the postprandial changes in male and female patients separately have not been determined yet. Gender differences in postprandial ketone bodies and C3 changes were investigated in normolipidemic patients and patients with untreated FCHL. Methods and Results—Thirty-two normolipidemic patients (16 female and 16 male) and 19 patients with untreated normolipidemia (9 female and 10 male) underwent an oral fat-loading test. Total and incremental areas under the curves (AUC and dAUC, respectively) after the oral fat load were calculated. Triglyceride AUC was similar between genders in each group. Normolipidemic female subjects showed a higher levels of dAUC-hydroxybutyric acid than male subjects (1.37±0.49 and 0.98±0.43 mmol · h/L). In FCHL, a similar trend was observed in female (1.92±0.38) compared with male (1.55±0.87) subjects. In contrast to normolipidemia, FCHL did not show a postprandial increase in C3, although C3 was higher in FCHL. Conclusions—Women have higher postprandial ketone bodies than men, probably reflecting enhanced postprandial hepatic FFA oxidation. In FCHL, both genders have higher postprandial ketone bodies and therefore higher hepatic FFA delivery. The higher fasting and postprandial C3 levels in FCHL may reflect resistance of the C3/acylation-stimulating protein system to promote peripheral fatty acid trapping.