Title: Triacylglycerol And Cardiovascular
Key words: serum lipoproteins, LDL,
HDL, CVD, plasma triglyceride, dyslipidaemia, insulin resistance syndrome, PUFAs
Date: December 1999
Category: 13. Specific Conditions
Author: Dr van Rhijn
Triacylglycerol And Cardiovascular
The modulatory effects of dietary
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.
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.
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
- Long-chain n-3 PUFAs (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 PUFAs 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 PUFAs 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.
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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