The kinetics of plasma free fatty acid and triglyceride transport in patients with idiopathic hypertriglyceridaemia and their relation to carbohydrate metabolism

Abstract. Plasma free fatty acid and triglyceride transport kinetics were assessed in 20 patients with idiopathic hypertriglyceridaemia. None of these patients had abnormal glucose tolerance. They included 10 patients in whom the serum triglyceride elevation was due to an increase in the circulating VLDL (Fredrickson Type IV) and 10 in whom the increase in plasma VLDL was associated with hyperchylomicronaemia (Fredrickson Type V). These were compared with a control group of 27 normal subjects.—Increased plasma triglyceride turnover with normal clearance was observed in the Type IV patients suggesting that the hypertriglyceridaemia in these patients was predominantly due to enhancement of plasma triglyceride production. The plasma triglyceride concentration correlated closely with the changes in triglyceride turnover rate.—Studies performed in the Type V patients showed an increase in the plasma triglyceride turnover rate in only 3 subjects, while in the remaining patients the turnover values were similar to those of the control subjects. The increase in serum triglyceride concentration found in some of the patients was due to an increase in plasma triglyceride production. However, in the majority of patients in this group impairment of plasma triglyceride clearance was the predominant abnormality.—In both hypertriglyceridaemic groups the plasma FFA flux was markedly increased and correlated significantly with the degree of hypertriglyceridaemia. The increase in triglyceride turnover observed in Type IV patients and some of the Type V patients correlated closely with the enhancement of plasma FFA flux suggesting that the increase in triglyceride production in these patients was secondary to enhanced lipolysis.—The plasma insulin response to an oral glucose load was markedly increased in both groups of hypertriglyceridaemic patients and correlated significantly with the elevation in serum triglyceride concentration. The plasma insulin response also correlated with the plasma free fatty acid turnover.—The results suggest that the initial lesion in these patients was related to insulin unresponsiveness in adipose tissue resulting in enhanced lipolysis with secondary changes in insulin secretion and plasma triglyceride transport kinetics.     

The mechanism of action of clofibrate and tetranicotinoylfructose (Bradilan) on the kinetics of plasma free fatty acid and triglyceride transport in type IV and type V hypertriglyceridaemia

Abstract. The kinetics of plasma free fatty acid and triglyceride transport were assessed in 20 patients with idiopathic hypertriglyceridaemia. These patients were subdivided according to lipoprotein pattern into Type IV and Type V patients. The effects of clofibrate therapy on plasma free fatty acid and triglyceride kinetics were assessed in these patients. Clofibrate produced a marked reduction in serum triglyceride associated with a significant reduction in triglyceride turnover as well as enhancement of triglyceride clearance. The reduction in triglyceride concentration produced by clofibrate was found to correlate with the reduction in free fatty acid turnover indicating that this drug decreased the availability of free fatty acid turnover indicating that this drug decreased the availability of free fatty acids for hepatic esterification. Clearance of endogenous plasma triglyceride was markedly enhanced in those patients in whom it was markedly impaired before treatment.—Having discontinued clofibrate for six weeks the same patients received bradilan (tetranicotinoylfructose) and kinetic measurements were repeated. It was evident that bradilan had a greater hypotriglyceridaemic effect than clofibrate in both groups of patients. The effect of bradilan was the result of inhibition of free fatty acid turnover and consequently a marked reduction in triglyceride turnover. Bradilan, unlike clofibrate, did not affect the mechanisms responsible for the clearance of plasma triglycerides.     

The Mechanism of Action of Clofibrate and Tetranicotinoylfructose (Bradilan) on the Kinetics of Plasma Free Fatty Acid and Triglyceride Transport in Type IV und Type V Hypertriglyceridaemia

Abstract. The kinetics of plasma free fatty acid and triglyceride transport were assessed in 20 patients with idiopathic hypertriglyceridaemia. These patients were subdivided according to lipoprotein pattern into Type IV and Type V patients. The effects of clofibrate therapy on plasma free fatty acid and triglyceride kinetics were assessed in these patients. Clofibrate produced a marked reduction in serum triglyceride associated with a significant reduction in triglyceride turnover as well as enhancement of triglyceride clearance. The reduction in triglyceride concentration produced by clofibrate was found to correlate with the reduction in free fatty acid turnover indicating that this drug decreased the availability of free fatty acid turnover indicating that this drug decreased the availability of free fatty acids for hepatic esterification. Clearance of endogenous plasma triglyceride was markedly enhanced in those patients in whom it was markedly impaired before treatment. – Having discontinued clofibrate for six weeks the same patients received bradilan (tetranicotinoylfructose) and kinetic measurements were repeated. It was evident that bradilan had a greater hypotriglyceridaemic effect than clofibrate in both groups of patients. The effect of bradilan was the result of inhibition of free fatty acid turnover and consequently a marked reduction in triglyceride turnover. Bradilan, unlike clofibrate, did not affect the mechanisms responsible for the clearance of plasma triglycerides.     

Metabolism of Very Low Density Lipoproteins in Hyperlipidaemia: Studies of Apolipoprotein B Kinetics in Man

The metabolism of very low density lipoprotein-B (VLDL-B) peptide was studied in nineteen subjects with endogenous hypertrigylceridaemia (Types V, IV and lib), three patients with heterozygous familial hyperbetalipoproteinaemia (Type Ila) and eight healthy subjects, by reinjecting autologous radioiodinated VLDL. The kinetics of VLDL-B peptide were followed. The mean turnover rate of VLDL-B peptide was significantly higher in the hypertriglyceridaemic group than in the control group but a considerable overlap in turnover rate was found between these groups. The patients with heterozygous familial hyperbetalipoproteinaemia had a normal turnover rate of VLDL-B peptide. A significant positive correlation was found between the turnover rate of VLDL-B peptide and VLDL-triglyceride concentration in the whole series. It is concluded that the underlying defect in endogenous hypertriglyceridaemia is heterogeneous. Overproduction of VLDL is a major determining factor in seme patients whereas a reduced clearance is the determining factor in others.     

Metabolism of very low density lipoproteins in hyperlipidaemia: studies of apolipoprotein B kinetics in man.

The metabolism of very low density lipoprotein-B (VLDL-B) peptide was studied in nineteen subjects with endogenous hypertriglyceridaemia (Types V, IV and IIb), three patients with heterozygous familial hyperbetalipoproteinaemia (Type IIa) and eight healthy subjects, by reinjecting autologous radioiodinated VLDL. The kinetics of VLDL-B peptide were followed. The mean turnover rate of VLDL-B peptide was significantly higher in the hypertriglyceridaemic group than in the control group but a considerable overlap in turnover rate was found between these groups. The patients with heterozygous familial hyperbetalipoproteinaemia had a normal turnover rate of VLDL-B peptide. A significant positive correlation was found between the turnover rate of VLDL-B peptide and VLDL-triglyceride concentration in the whole series. It is concluded that the underlying defect in endogenous hypertriglyceridaemia is heterogeneous. Overproduction of VLDL is a major determining factor in some patients whereas a reduced clearance is the determining factor in others.     

Very low density lipoprotein overproduction in genetic forms of hypertriglyceridaemia

Abstract. Very low density lipoprotein kinetic parameters were compared in familial hypertriglyceridaemia and familial combined hyperlipidaemia, two distinct genetic forms of hypertriglyceridaemia. Very low density lipoprotein apoprotein B turnover rate was greater in hypertriglyceridaemic subjects with familial combined hyperlipidaemia (099±0–27 mg/kg/h; n = 5; P < 0005) and also in familial hypertriglyceridaemia (0–74±0–10; n = 6; P < 0–005) than in age and weight matched non-hyperlipidaemic controls (0–54±0–21; n = 6), suggesting that the hypertriglyceridaemia seen in both genetic disorders was due to very low density lipoprotein overproduction. Very low density lipoprotein apoprotein B turnover rate was greater in familial combined hyperlipidaemia than in familial hypertriglyceridaemia while plasma triglyceride turnover was higher in familial hypertriglyceridaemia. This disparity in the turnover rates of apoprotein B and triglyceride between these disorders was accompanied by a higher very low density lipoprotein triglyceride/apoprotein B ratio in familial hypertriglyceridaemia than in familial combined hyperlipidaemia ( P < 0001) and in normals ( P < 0–005).
The findings suggest that the hypertriglyceridaemia of familial combined hyperlipidaemia is due to overproduction of very low density lipoprotein of normal composition, while that of familial hypertriglyceridaemia is due to oversecretion of triglyceride-enriched very low density lipoprotein.     

Lipid and carbohydrate metabolism in uraemia

Lipid and carbohydrate metabolism variables were studied in twenty-eight patients with chronic renal failure (mean GFR 7.7 +/- 2.5 ml/min) and uraemic symptoms. 71% of the patients had hypertriglyceridaemia (greater than or equal to 2.2 mmol/l). Total serum cholesterol was normal while VLDL cholesterol was high and alpha-lipoprotein cholesterol was low. The fractional elimination rate of Intralipid was low and inversely correlated to serum triglyceride levels. Intravenous glucose tolerance was reduced with normal or slightly increased fasting blood glucose and insulin values before and during the test. Serum triglycerides were correlated to plasma insulin but not to residual renal function or serum urea levels. The cause of hypertriglyceridaemia and lowering of alpha-Lp cholesterol is not unequivocally clear. Present evidence indicate that retarded catabloism of triglyceride-rich lipoproteins is important but accentuated release of triglyceride-rich lipoproteins may have occurred in a number of cases. The commonly used treatment with beta-blocking agents for hypertension in chronic renal failure may accentuate certain of the metabolic responses in uraemia.     

Regulation of plasma lecithin:cholesterol acyltransferase in man. I. Increased activity in primary hypertriglyceridemia.

Patients with primary hypertriglyceridemia have been reported to manifest increased in vivo turnover of plasma cholesteryl esters. To ascertain if this is due to plasma lecithin:cholesterol acyltransferase (LCAT) and to explore a possible link between triglyceride and cholesteryl ester turnover, we have measured LCAT in 15 patients with Type IV, 2 with Type V, 1 with Type III, and 9 with Type II B hyperlipoproteinemia. LCAT was significantly elevated (p less than 0.001) in hypertriglyceridemic subjects, regardless of lipoprotein pattern. In the Type IV group, but not in normal subjects, LCAT correlated significantly with measures of very low-density lipoprotein (VLDL) elevation, including plasma triglycerides and particularly VLDL-unesterified cholesterol, but not with body weight or substrate high-density lipoprotein (HDL) lipid levels. On repeated determinations in individual subjects, a relationship between triglyceride fluctuations and LCAT could be demonstrated in only one subject over an extreme range of triglyceride levels. Analysis of lipoprotein lipids revealed that the ester:free cholesterol ratio in VLDL was increased in hypertriglyceridemia, but was not correlated with enzyme level. In vitro removal of endogenous VLDL or addition of VLDL from lipemic plasmas to normal plasmas was without effect on enzyme activity. Regulation of enzyme activity does not appear to be a direct function of VLDL level.     

Sex Difference in the Kinetics of Triglyceride Metabolism in Normal and Hypertriglyceridaemic Human Subjects

Abstract. Several years ago we demonstrated in man that increasing plasma very low density lipoprotein (VLDL) triglyceride (TG) concentrations were associated with increasing VLDL-TG production rates, and that this relationship described a rectangular hyperbola which could be characterized in terms of enzyme kinetics. Utilizing this approach Nikkilä and Kekki confirmed these observations in a large group of normal subjects. Moreover, after analyzing the Km and Vmax values of their subjects they noted a striking and important sex difference: females were found to have significantly lower Km values than men, whereas the Vmax values for the two groups were the same. This indicates that for a given VLDL-TG production rate, females will have lower plasma TG concentrations. We have now studied 53 subjects with widely varying plasma TG concentrations, and have been able to detect a similar sex difference in subjects with hypertriglyceridaemia. Furthermore, we have noted a highly significant direct relationship between TG concentration and production in both sexes, and have found no relationship between an individual's Km value and his coexisting plasma TG level. These results allow us to conclude that: 1) the sex difference in TG kinetics which Nikkilä and Kekki originally note in normals can now be extended to include hypertriglyceridaemic subjects, and 2) in general, overproduction, and not underutilization, is the initiating event in most cases of hypertriglyceridaemia.     

Plasma Triglyceride Metabolism in the Adult Nephrotic Syndrome

Abstract. The kinetic parameters of plasma triglyceride metabolism were determined in 14 adult subjects with the nephrotic syndrome by endogenous labelling of circulating triglyceride with tritiated glycerol. The triglyceride production (turnover) rate and the apparent K_m of removal were calculated from the slope of the radioactivity disappearance curve and compared to a normal control material studied previously. Plotting of the individual data in a log scale of triglyceride concentration versus turnover with the normal area and saturation curves in the background allowed a detailed characterization of the nature of kinetic alterations occurring in disease. It was found that in the majority of cases with the nephrotic syndrome the plasma triglyceride concentration and rate of influx are slightly above normal. However, the apparent K_m of removal was significantly increased suggesting that efflux may also be somewhat impaired. In four cases the plasma triglyceride was produced at a rate which exceeded the value predicted by the normal saturation curves and it is believed that an uncontrolled overproduction of plasma triglyceride was present in these cases.—Complete remission of disease in one case brought both triglyceride concentration and turnover rate rapidly to normal values. An eight-hour infusion of human serum albumin in another patient promptly caused a return of high triglyceride turnover to normal.— The primary change behind the nephrotic hypertriglyceridaemia seems to be a controlled increase of plasma triglyceride synthesis. In some cases, however, this overproduction occurs in an uncontrolled fashion and in a number of patients decrease of removal efficiency contributes to the development of hyperglyceridaemia. All of these changes can be explained on the basis of an increased FFA/albumin molar ratio in plasma giving rise to the elevation of unbound FFA fraction.     

Post-heparin plasma lipoprotein lipase and hepatic lipase in normal subjects and in patients with hypertriglyceridaemia: correlations to sex, age and various parameters of triglyceride metabolism.

1. A selective immunochemical method was used to measure post-heparin plasma lipoprotein lipase and hepatic lipase activity in eighty-two normal subjects and in twenty patients with type IIb, IV or V hypertriglyceridaemia. In twenty-six normal subjects the activity of post-heparin plasma lipases was compared with the kinetic parameters of endogenous plasma triglyceride metabolism. 2. The activity of post-heparin lipoprotein lipase was significantly higher in normal females than in males, whereas the activity of hepatic lipase showed an opposite sex ratio. The activity of lipoprotein lipase decreased with age both in males and females, whereas no significant age variation was observed in the activity of hepatic lipase. 3. In normal subjects a highly significant negative correlation was present in both sexes between the activity of post-heparin plasma lipoprotein lipase and fasting serum triglyceride concentration, but not between the activity of post-heparin hepatic lipase and serum triglycerides. 4. The fractional removal rate of endogenous triglycerides was positively correlated to the activity of lipoprotein lipase but not to the activity of hepatic lipase. No relationship was found between the activities of post-heparin plasma lipases and the absolute turnover of serum triglycerides. 5. The mean activity of post-heparin plasma lipo-protein lipase was significantly lower in subjects with hyperprebetalipoproteinaemia than in normal individuals. However, many hypertriglyceridaemic patients had lipoprotein lipase within the normal range and there was no correlation between serum triglyceride concentration and the activity of post-heparin lipases. 6. All three patients with fasting chylomicronaemia had low post-heparin lipoprotein lipase activity. Several subjects with high post-heparin plasma hepatic lipase activity were present in the group with hyperprebetalipoproteinaemia, but the mean value of the hepatic lipase was not significantly different from normal.     

Initial cholesterol esterification rate in hyperlipoproteinaemia: effects of triglyceride-rich lipoproteins.

The initial cholesterol esterification rate (LCAT activity) was determined in ninety-four hyperlipidaemic subjects. LCAT activity was elevated in hypertriglyceridaemia, whereas patients with hypercholesterolaemia had normal activities. In hypertriglyceridaemic subjects LCAT activity correlated with the concentrations of d less than 1.006 lipoproteins, plasma triglycerides, cholesterol and cholesterol esters and phospholipid levels. Addition of d less than 1.006 lipoprotein to normal plasma resulted in a dose dependent stimulation of enzyme activity with a sigmoidal response curve. When the d less than 1.006 lipoproteins were removed from hypertriglyceridaemic plasma by ultracentrifugation, the enzyme activity in the residual d greater than 1.006 fraction dropped, but still was higher than in normal plasma and correlated with the amount of d less than 1.006 lipoproteins originally present. Thus, high LCAT activity in hypertriglyceridaemia cannot be explained solely by the presence of an increased d less than 1.006 lipoprotein concentration. An increase of enzyme concentration or changes in concentration or composition of other lipoproteins (high density lipoproteins) may contribute to the high LCAT activity in hypertriglyceridaemia.     

Splanchnic Secretion Rates of Plasma Triglycerides and Total and Splanchnic Turnover of Plasma Free Fatty Acids in Men with Normo- and Hypertriglyceridaemia

Abstract. Plasma triglyceride (TG) “turnover rates” were estimated in the fasting state in three different ways: splanchnic chemical TG secretion, splanchnic isotope TG secretion and plasma TG clearance. Forty-two men with a wide range of fasting plasma TG concentrations, from 0.53 to 16.50 mmol/l were investigated. A constant intravenous infusion of albumin-bound ³H-labelled palmitate was given and blood was simultaneously sampled from the hepatic vein and an artery for determination of hepatic venous-arterial differences of labelled and unlabelled plasma TG. In addition total and splanchnic turnovers of plasma FFA were measured. Similar values were obtained for plasma TG “turnover rate” by the splanchnic chemical TG secretion and the plasma TG clearance method. The values for these two methods varied between 3 and 74 μmol/min. and m² body surface area, except for two cases who had considerably higher values. The splanchnic isotope TG secretion method gave lower values varying from 1 to 34 μmol/min. and m² body surface area. This method probably measures only that fraction of the splanchnic TG secretion which is derived from plasma FFA. No correlations were found among normotriglyceridaemic subjects between plasma total TG or VLDL-TG concentrations and plasma TG “turnover rates” measured by any of the three methods. For patients with hypertriglyceridaemia significant positive correlations were found between plasma VLDL-TG concentrations and plasma “turnover rates”. The “fractional turnover rate” decreased with increasing TG levels in an apparently hyperbolic fashion. The results suggest an impaired plasma TG removal capacity in patients with hypertriglyceridaemia. In 7 out of 14 patients the plasma TG “turnover rates” were in the upper part of the normal range and seemed to have contributed to the hypertriglyceridaemia in these patients. Plasma FFA turnover rate ranged between 102 and 439 μmol/min. and m² body surface area. On the average splanchnic FFA mobilization and uptake were about 30 and 60 per cent respectively of total FFA turnover rate. Significant positive correlations were found for the interrelationships between the three plasma FFA total and splanchnic transport parameters. Significant positive correlations were found between the three plasma TG “turnover rates” and total and splanchnic turnover of plasma FFA in subjects with normal plasma TG concentrations. Some patients with hypertriglyceridaemia fell outside the intervals of 99 per cent confidence of the regression analyses for the normo-triglyceridaemic subjects. This group had higher TG “turnover rates” than “expected” from plasma FFA turnover rates and may represent a distinctive group of hypertriglyceridaemia from the point of view of pathogenesis. It was concluded that all patients with hypertriglyceridaemia who were investigated had decreased “fractional turnover rates” of plasma TG indicating a decreased removal capacity which might be a primary cause of the hypertriglyceridaemia although inflow of plasma TG seemed to be an essential contributing factor in half the number of patients.     

Sex Difference in the Kinetics of Triglyceride Metabolism in Normal and Hypertriglyceridaemic Human Subjects

Abstract. Several years ago we demonstrated in man that increasing plasma very low density lipoprotein (VLDL) triglyceride (TG) concentrations were associated with increasing VLDL-TG production rates, and that this relationship described a rectangular hyperbola which could be characterized in terms of enzyme kinetics. Utilizing this approach Nikkila and Kekki confirmed these observations in a large group of normal subjects. Moreover, after analyzing the Km and Vmax values of their subjects they noted a striking and important sex difference: females were found to have significantly lower Km values than men, whereas the Vmax values for the two groups were the same. This indicates that for a given VLDL-TG production rate, females will have lower plasma TG concentrations. We have now studied 53 subjects with widely varying plasma TG concentrations, and have been able to detect a similar sex difference in subjects with hypertriglyceridaemia. Furthermore, we have noted a highly significant direct relationship between TG concentration and production in both sexes, and have found no relationship between an individual's Km value and his coexisting plasma TG level. These results allow us to conclude that: 1) the sex difference in TG kinetics which Nikkila and Kekki originally note in normals can now be extended to include hypertriglyceridaemic subjects, and 2) in general, overproduction, and not underutilization, is the initiating event in most cases of hypertrigiyceridaemia.     

The Metabolism of Low Density Lipoprotein in Endogenous Hypertriglyceridaemia

The metabolism of low density lipoprotein (LDL) was studied in eighteen hypertriglyceridaemic patients by injecting autologous radioiodinated LDL. Over 95 % of the label was bound to the protein moiety of LDL and therefore the metabolic data reflect the fate and distribution of LDL apoprotein (apo B). The hypertriglyceridaemic subjects included ten with Type V, five with Type IV, two with Type III and one with Type lib hyperlipoproteinaemia. For comparison identical studies were carried out in seven normal subjects and five patients with heterozygous familial hyperbetalipoproteinaemia (Type Ila). The groups differed considerably in mean LDL-cholesterol concentration. The patients with Type V lipoprotein pattern had significantly lower LDL-cholesterol concentration (mean 0.754 g/1) than the normal group (mean 1.237 g/1). Raised LDL-cholesterol levels were observed in all patients with heterozygous familial hyperbetalipoproteinaemia. The synthetic rate of LDL-apoprotein was found to be similar in all three groups (hypertriglyceridaemic, normal and hypercholesterolaemic). The highest synthetic rate was observed in the patient with Type lib pattern. However, the fractional catabolic rate (FCR) of LDL-apoprotein differed significantly. The highest mean FCR was found in the Type V group (0.65 ± 0.17 day^-1) compared with 0.41 ± 0.09 day^-1 in the normal group and 0.185 + 0.05 day^-1 in the Type Ila group. A strong inverse correlation was found between FCR and LDL apoprotein concentration in the whole series (r = - 0.90, p < 0.001) as well as within the Type V group (r = - 0.87, p < 0.01). These data indicate that the low plasma levels of LDL frequently observed in patients with very high plasma triglyceride levels are due to a high removal rate of LDL in these patients rather than to abnormal LDL synthesis.     

The Asn-291→Ser and Ser-477→Stop mutations of the lipoprotein lipase gene and their significance for lipid metabolism in patients with hypertriglyceridaemia

We examined 99 Finnish patients whose serum fasting triglycerides (TG) had exceeded 6.0 mmol L^?1, with special interest to their lipid, lipoprotein and post-heparin plasma lipase activities. The control group consisted of 75 healthy individuals. We also determined the frequency of the Asn-291→Ser and Ser-447→Stop mutations both in hypertriglyceridaemic (HTG) subjects and in control subjects. A total of 51 of the original 99 hypertriglyceridaemic patients still had TG > 6.0 mmol L^?1 when measured a second time. They are referred to as persistently hypertriglyceridaemic subjects (pHTG). The remaining 48 subjects had TG < 6.0 mmol L^?1 in the second measurement and are referred to as sporadically hypertriglyceridaemic subjects (sHTG). The allelic frequencies of the Ser-447→Stop mutation in the total HTG and sHTG groups were similar to the frequencies present in the control group, but lower in pHTG patients compared with the control group (0.049 vs. 0.153, χ² = 6.63, P < 0.05). The Asn-291→Ser mutation was more frequent in HTG group than in the control group (0.0606 vs. 0.013, χ² = 4.86, P < 0.05). This difference was due to the higher frequency of the minor allele of Asn-291→Ser in the cohort with persistent hypertriglyceridaemia compared with the control group (0.088 vs. 0.013, χ² = 8.00, P < 0.01 ). The highest frequency (0.114) of the minor allele of Asn-291→Ser was found in type 2 diabetic patients with persistent hypertriglyceridaemia. The carrier status of Asn-291→Ser or Ser-447→Stop did not predict either post-heparin plasma lipoprotein lipase (LPL) activities or lipid and lipoprotein levels in any of the groups studied. Our data suggest that overproduction of very low-density lipoproteins (VLDL) is a more important cause of hypertriglyceridaemia in the Finns than is the LPL deficiency.     

Cholesterol metabolism in hypertriglyceridaemia and the effects of treatment.

The faecal output of bile acids and endogenous neutral steroids was increased in three hypertriglyceridaemic patients. One patient had familail type IIb, one had type IV and the third had type V hyperlipoproteinaemia. The hyperlipidaemia in the type IV and type V patients was associated with diabetes and a high alcohol intake. The plasma cholesterol and triglyceride concentrations and the faecal output of bile acids decreased significantly when the type IIb patient was given D-thyroxine plus propranolol, and when the type IV and type V patients were treated by withdrawal of alcohol, a low=carbohydrate diet and insulin or glibenclamide. The findings are discussed in relation to the possibility that hypertriglyceridaemia and increased bile acid synthesis in these patients have a common metabolic origin.     

Initial cholesterol esterif ication rate in hyperlipoproteinaemia: effects of triglyceride-rich Iipoproteins

Abstract. The initial cholesterol esterification rate (LCAT activity) was determined in ninety-four hyper-lipidaemic subjects. LCAT activity was elevated in hypertriglyceridaemia, whereas patients with hyper-cholesterolaemia had normal activities. In hypertri-glyceridaemic subjects LCAT activity correlated with the concentrations of d 1.006 lipoproteins, plasma triglycerides, cholesterol and cholesterol esters and phospholipid levels. Addition of d < 1.006 lipoproteinto normal plasma resulted in a dose dependent stimulation of enzyme activity with a sigmoidal response curve. When the d < 1.006 lipoproteins were removed from hypertriglyceridaemic plasma by ultracentrifugation, the enzyme activity in the residual d > 1.006 fraction dropped, but still was higher than in normal plasma and correlated with the amount of d 1.006 lipoproteins originally present. Thus, high LCAT activity in hypertriglyceridaemia cannot be explained solely by the presence of an increased d < 1.006 lipoprotein concentration. An increase of enzyme concentration or changes in concentration or composition of other lipoproteins (high density lipoproteins) may contribute to the high LCAT activity in hypertriglyceridaemia.     

Immunonephelometric quantitation of the apolipoprotein C-III in human plasma

A quantitative assay, based on endpoint immunonephelometry, was developed for human apolipoprotein C-III (Apo C-III) in plasma and lipoprotein fractions. The standard curve was constructed either with purified Apo C-III2 as a primary standard or with plasma as a secondary standard. It was linear between 50 and 400 ng Apo C-III per sample, corresponding to 1 microliter undiluted plasma. The intra- and interassay coefficients of variation (CV values) were 2.2 and 6.3%, respectively. The Apo C-III immunoreactivity was not influenced by detergents, denaturants nor by delipidation. The use of a non-ionic detergent (Apovax, 0.1 g/l) avoided the need for organic solvent extraction for plasma containing up to 4 g of triglycerides/l by reducing the sample turbidity. As measured in 126 normolipidemic subjects, the plasma Apo C-III concentration was 0.118 +/- 0.028 g/l (mean +/- SD). Apo C-III concentrations were only slightly elevated in patients with Fredrickson type IIa hyperlipoproteinaemia. The Apo C-III levels were nearly 3 times higher in type I, IIb, III and IV patients, while subjects with type V hyperlipaemia had about a 5-fold increase in Apo C-III compared to the healthy. The plasma Apo C-III values were strongly correlated with the plasma triglyceride concentrations (r = 0.80, n = 201). The Apo C-III distribution among the various lipoprotein fractions showed a higher proportion of Apo C-III in VLDL in hypertriglyceridaemic subjects compared to normolipaemic subjects.     

Investigations into the haemorheological significance of postprandial and fasting hypertriglyceridaemia

Abstract. Two study designs were conceived to evaluate the rheological significance of hypertriglyceridaemia. We first investigated the course of serum- (SV) and plasma viscosity (PV) and erythrocyte aggregation in serum (SEA) and plasma (PEA) of healthy normoli-pidaemic individuals over 4 h after a fatty rich meal, in native material and after removal of triglyceride rich lipoproteins by centrifugation. Secondly, blood from patients with untreated hypertriglyceridaemia was investigated under fasting conditions. PEA and SEA increased in parallel with postprandial triglycerides (+135 mg dl^-1), but the effect on PEA was more pronounced (+ 0.8 abs% increase; 2 h after the meal) as compared to SEA (+ 0.4 abs% increase). PV and SV increased in parallel to the same extent (+ 0.05 mPas). In the triglyceride poor infranatant no significant changes occurred. In fasting plasma PEA and PV were significantly lower (1.1abs% and PV 0.04 mPas respectively) in infranatant than in native plasma, while only small differences in triglyceride (mostly VLDL) were observed. This phenomenon was barely detectable in serum samples.
We conclude that triglyceride rich lipoproteins have a profound influence on haemorheological parameters, and that fibrinogen in particular, potentiates the effect of large fasting VLDL on plasma viscosity and erythrocyte aggregation.