D. R. Illingworth

Polyunsaturated fatty acids, hyperlipidemia, and thrombosis.

Polyunsaturated Fatty Acid Families and Interrelationships Omega-6 Fatty Acids and Plasma Lipids Plasma Cholesterol Plasma Triglycerlde Plasma LJpoprotelns and Apolipoproteins Hypolipldemic Mechanisms of Linoleic Acid Decrease in Cholesterol Absorption Increase in Fecal Steroid Excretion Reduced Cholesterol Synthesis and the Transfer of Cholesterol to the Tissues Decrease in Cholesterol Content of LJpoproteins Changes in the Rates of Synthesis and Catabolism of LJpoproteins Membrane Fatty Acid Composition and Upoprotein Metabolism

Inhibition of low density lipoprotein synthesis by dietary omega-3 fatty acids in humans.

Diets rich in omega-3 fatty acids derived from fish oils lower the plasma concentrations of low density lipoproteins (LDL) and very low density lipoproteins in humans. The present study was designed to examine the mechanism(s) by which diets enriched in omega-3 fatty acids reduce plasma LDL cholesterol levels in normal subjects. Seven healthy volunteers with normal plasma lipid levels consumed two metabolically controlled diets for a period of 4 weeks each. The control diet contained predominantly saturated and monounsaturated fatty acids, whereas the fish-oil diet contained 24 gm of omega-3 fatty acids per day. The total fat and cholesterol content of the two diets were similar for each subject. Total and LDL cholesterol levels decreased from 162 +/- 26 mg/dl and 103 +/- 27 mg/dl on the control diet to 124 +/- 26 mg/dl and 82 +/- 27 mg/dl on the omega-3-rich diet. Triglyceride levels fell from 91 +/- 34 mg/dl to 52 +/- 19 mg/dl. Kinetic studies of 125I-LDL metabolism disclosed a significantly lower rate of synthesis of LDL apoprotein B on the omega-3-rich diet (9.5 +/- 1.3 mg/kg/day) as compared to the control diet (13.6 +/- 3.7 mg/kg/day; p less than 0.05). In contrast, the fractional catabolic rate was similar on both diets. We conclude that dietary omega-3 fatty acids lower plasma LDL levels in normal human subjects by reducing the rate of synthesis of apoprotein B.

Hypolipidaemic effects of n‐3 fatty acids in primary hyperlipoproteinaemia

Abstract. The influence of fish oils rich in n‐3 fatty acids on plasma lipid and lipoprotein concentrations in patients with primary hyperlipoproteinaemia is reviewed. When used as a dietary supplement, n‐3 fatty acids exert their greatest effect on the concentrations of triglyceride‐rich lipoproteins and these effects are dose dependent. Low doses of n‐3 fatty acids reduce plasma triglyceride concentrations in patients with phenotypic type IV, type V and type IIB hyperlipoproteinaemia, but concurrently result in modest increases in the plasma concentrations of low density lipoprotein (LDL). With very high doses plasma concentrations of LDL cholesterol decrease in patients with the type IIB phenotype. At low doses n‐3 fatty acids do not significantly lower concentrations of LDL cholesterol in patients with primary hypercholesterolaemia whereas at higher doses a modest LDL lowering effect is achieved. The results indicate that the therapeutic potential of n‐3 fatty acids as hypolipidaemic agents is greatest in patients with hypertriglyceridaemia.

Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin.

We evaluated the effects of different doses of lovastatin, a competitive Inhibitor of 3-hydroxy-3-methy1glutary1 coenzyme A reductase (HMG CoA reductase) and the rate-limiting enzyme in cholesterol biosynthesis, on parameters of cholesterol homeostasis In freshly Isolated mononuclear leukocytes from 19 patients with heterozygous familial hypercholesterolemia. Patients were treated with sequentially Increasing doses of lovastatin (10 to 80 mg/day In a twice-daily regimen). The in vitro activity of HMG CoA reductase and cholesterol synthesis from 2-14C-acetate was determined In mononuclear cells obtained under steady-state conditions after patients had spent 6 weeks on doses of 20, 40, or 80 mg/day. The total and high affinity degradation of 12sHow density llpoprotein (LDL) was determined at baseline and on lovastatin at a dose of 80 mg/day. LDL cholesterol levels fell progressively on lovastatin (38% reduction on 80 mg dally, /K0.005). These changes were paralleled by a 121% Increase In the activity of HMG CoA reductase (p<0.05) and a 39% increase In cholesterol synthesis from 2-14C-acetate (p<0.005). Total and high affinity degradation of 12SI-LOL Increased from 27±3.3 and 12.1 ±1.6 ng/4 × 10” cells/4 hours on the diet only to 69.7±7.2 and 32.9±3.6 ng/4 × 10* cells/4 hours, respectively, (mean±SEM) In mononuclear cells Isolated from patients on 80 mg of lovastatin daily (p < 0.005). We conclude that the hypocnotesterotemlc effects of chronic lovastatin therapy are accompanied by an Increase In high affinity degradation of LDL and an Increased capacity for cholesterol biosynthesis In freshly Isolated mononuclear leukocytes.

Increased Activity of Factor VII and Factor VII-Phospholipid Complex Measured Using a Normotest System in Subjects with Hyperlipidemia

Coagulation factor VII and factor VII-phospholipid complex (factor VIIpl), an activated form of factor VII, were measured using a Normotest system in 128 patients with various types of hyperlipoproteinemias and in 45 control subjects. A positive correlation was found between both factors VII (p less than 0.001) and VIIpl (p less than 0.0001) and serum triglycerides. Similar correlations were established with very low density lipoproteins. A positive correlation was also observed between factor VIIpl and total cholesterol, whereas inverse correlations were found with high-density lipoproteins for both factors VII and VIIpl. No positive correlation could be found between low-density lipoproteins and factors VII and VIIpl. This study has shown that patients with hyperlipoproteinemias associated with high serum triglyceride levels, with or without high cholesterol levels, have increased activity of factors VII and VIIpl, both previously associated with an increased risk of coronary heart disease.