Title: Triacylglycerol And Cardiovascular Risk.

Key words: serum lipoproteins, LDL, HDL, CVD, plasma triglyceride, dyslipidaemia, insulin resistance syndrome, PUFAs

Date: December 1999

Category: 13. Specific Conditions

Type: Article

Author: Dr van Rhijn

Triacylglycerol And Cardiovascular Risk.

The modulatory effects of dietary fatty acids

 

Introduction

There is a wealth of evidence linking raised triacylglycerol (TAG) levels1 with the generation of pro-atherogenic changes in serum lipoproteins, especially the formation of small dense low density lipoprotein (LDL)2 and a reduced level of cardio protective high density lipoproteins (HDL) causing a subsequently increased risk of cardiovascular disease (CVD)3. The underlying mechanisms for this are discussed here along with the modulatory effect of dietary fatty acids.

Endothelial Lipases

Lipoprotein Lipase (LPL) acts primarily on triglyceride-rich lipoproteins (TGRL) of dietary (chylomicrons) and hepatic origin very low-density lipids (VLDL). LPL activity is essential for the clearance of chylomicrons and the conversion of large VLDL (VLDL1) into small VLDL (VLDL2) and further into IDL. Hepatic lipase (HL) facilitates the conversion of IDL into large LDL and act on smaller VLDL particles as well as promoting interconnections between LDL subclasses4.

The transfer of cholesteryl ester from HDL to LDL links these two pathways via the action of cholesteryl ester transfer protein (CETP), which converts small LDL into larger LDL5. Plasma LDL is structurally heterogeneous and consists of smaller sub fractions (LDL-I, II & III)6, with a positive relationship between LDL cholesterol and plasma triglyceride where LDL-III is associated with raised plasma triglyceride.

There is an increase in the buoyant density of LDL and the persistence of small, dense LDL in patients with familial combined hyperlipidaemia7. The lowering of plasma triglyceride (with fenofibrate) is associated with an increase in synthetic input and clearance of LDL (from the slowly turning over metabolic pool [Pool B]) and redistribution towards lighter LDL-I and LDL-II8 (in the rapidly turning over metabolic pool [Pool A]).

Plasma triglyceride appears to be the major regulatory determinant of VLDL and LDL subclass distribution, mediated through postprandial lipoproteins, endothelial lipase and lipid transfer proteins, all subject to metabolic control by insulin.

Mechanism

This high-risk dyslipidaemia, collectively known as an atherogenic lipoprotein phenotype (ALP)9, has a strong genetic basis but is also thought to be secondary to the insulin resistance syndrome. It develops independently of serum cholesterol or even below the clinically recognised limits of action of serum triglyceride (TG - 1.5 mmol/l), and is therefore often unrecognised and untreated. Post-prandial insulin failure can result in an oversupply of non-esterified fatty acids (NEFA) and subsequent increased synthesis of TGRL10 and secretion of abnormally large, TG-rich VLDL11, and small dense LDL12.

This is responsible for hypertriglyceridaemia (HTG) above 1.5 mmol/l, accompanied by reduced HDL cholesterol concentrations, as found in obesity and non-insulin dependent diabetes mellitus (NIDDM)11a. The large, TG-rich VLDL compete ineffectively14 with chylomicrons for clearance by the enzyme LPL, its activity also impaired in insulin resistant states and is hydrolysed by HL, resulting in a reduction in LDL particle size.

There is therefore a common15, saturable pathway for the removal of postprandial lipoproteins, suggesting that the large VLDL is the main competitor of chylomicrons rather than the small VLDL. Hypertrigyceridaemic coronary artery diseased patients showed enhanced postprandial lipaemia and a deficiency of C apolipoprotein in TGRL that mediates the action of LPL16. Repeated exposure to enhanced post-prandial lipaemia over extended periods of time may provide a metabolic stimulus for the development of small, dense LDL17. Decreased post-heparin LPL18 and increased HL activity19 has been found in the insulin-resistant state20 and obesity21 has been associated with low plasma HDL22 and high LDL (III23) subclass24 concentrations in CHD patients with high plasma triglyceride concentrations25. The exchange of cholesteryl esters from LDL for triglycerides in TGRL particles (neutral lipid exchange)26 mediated through the action of CETP and endothelial lipases may be the mechanism to explain these associations27 and generation of small dense LDL species28.

Postprandially, the clearance of chylomicrons remnants, HL and insulin resistance are predictors for the formation of LDL-III in NIDDM29. HL is therefore an important enzyme in the remodelling of lipoproteins and VLDL. There is a significant increase in lipid-associated atherogenic risk with this increased LDL/HDL ratio.

Small, dense LDL has a lower binding affinity30 for the apoprotein B (apoB) region recognised by the LDL receptor, in contrast to the lighter LDL-II which has a greater binding affinity, and therefore a greater receptor-mediated clearance of LDL31. Most of the serum cholesterol is carried by LDL and delivers it to cells via their surface protein apoB and HDL with its characteristic protein apoA. Small dense LDL shows an increased residence time in the intravascular compartment (less binding to the physiological cell surface receptor), resulting in more rapid infiltration (due to its size) into the intimal lining of the artery wall32, subsequent high affinity binding to arterial proteoglycans and susceptibility to LDL oxidation, thus accelerating the formation of foam cells, a depositional endpoint for serum cholesterol, resulting in arteriosclerosis. However, a predominance of small, dense LDL and hyper-apoprotein B (absolute number of LDL particles) does not always co-exist in free-living groups, and it may well be the latter that is associated with increased CVD33 when plasma triacylglycerol exceeds 2,5 mmol/l.

Polyunsaturated Fatty Acid Influence (PUFA’s)

Long-chain n-3 PUFA’s (fish oils) have a potent TG-lowering action by suppression of TG synthesis in the liver, thereby reducing the production of VLDL and the concentration of small, denser LDL particles in favour of larger, less dense LDL species, as well as reducing apolipoprotein B and the magnitude and duration of the post-prandial lipaemic response34. Evidence is emerging that they may stimulate the activity of the insulin responsive enzyme LPL and that their beneficial effects on lipid metabolism are mediated through the stimulation and repression of insulin responsive genes. Supplementation with n-3 PUFA’s have been shown to prevent ventricular arrhythmias35, cardiac arrest, have an anti-thrombotic36 effect, reduce endothelial inflammatory response and blood pressure37, therefore decreasing the CVD risk and mortality in patients who recently survived a myocardial infarction38. They are active in reducing postprandial and fasting plasma triglyceride concentrations39, 40, VLDL synthesis and a fall in LDL but do not lower total serum cholesterol. Consumption of oily fish reduced mortality by 50% in CVD (Zutphen study41) and by 29% in post myocardial infarct patients (Dart trial42).

Dietary trans fatty acids may have a greater responsibility for the link between dietary fat and CVD than saturated fatty acids (SFA's)43, due to their association with an increase in serum LDL-cholesterol, decrease in HDL-cholesterol and an elevation in the concentration of the LDL related lipoprotein A44, and is an independent risk factor for CHD45 and mortality.

Replacement of SFA with monounsaturated fatty acids (MUFA's) or n-6 PUFA’s have a protective effect against LDL oxidation and reduce the plasma LDL-C and TC:HDL-C ratio. These replacements have been shown to reduce CVD risk in epidemiological studies. Hypercholesterolaemia, due to a diet high in fat (especially saturated), is an important risk factor for the development of CVD (Keys Seven Country Study46) and statin drug treatment has caused reported reductions of 20-25% in serum cholesterol and a significant reduction in overall mortality47.

Conclusion

Triacylglycerol remains an independent risk factor for CVD48 and prevention with long-chain n-3 PUFA's49 may prove beneficial for the majority of the population with raised serum TAG levels. This may also be a potent tool in the treatment of hypertriglyceridaemia or combined hyperlipidaemia.

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