The two major lipids in plasma-cholesterol and triglyceride—have essential functions in the overall structure and fuel economy of the body.
Cholesterol
In its free, unesterified form cholesterol is a major component (together with phospolipid) of cell membranes. Its presence helps to stabilize membrane fluidity and therefore, the barrier between cell and environment. Cholesterol is also important as a precursor of steroid hormones and of bile acids. Cholesterol present in the plasma and extracellular fluid is largely in the esterified form.
Triglycerides
Triglycerides are produced by the esterification of glycerol with three fatty acid molecules. They are the body’s major energy store, particularly in adipose tissue. Fatty acids are released through the action of hormone-sensitive lipase, an enzyme that becomes active during fasting when insulin levels are low. They can be utilized directly as fuel by muscle or by other tissues,including brain, following partial oxidation to ketone bodies in the liver.
Triglyceride and cholesterol ester are insoluble in the aqueous environment of the plasma and are solubilized by their incorporation into lipoproteins.
Lipoprotein Structure
There are several different lipoprotein species found in plasma but their basic structures are similar. The insoluble lipid (cholesterol ester and triglyceride) forms a central core in the form of a lipid droplet. This is surrounded by an outer monolayer of molecules such as free cholesterol,phospholipids and proteins termed apoproteins, which give the complexes their name. These molecules are able to sit at the water/fat interface because they are partly water-soluble and partly lipid-soluble.
Apoproteins
Apoproteins not only stabilize lipoprotein structure but also have other important regulatory functions in lipoprotein metabolism. Apoproteins B 100 and E are necessary for the binding of lipoproteins to cellular receptors, whereas apoproteins A-I and C-II are activators of enzymes important in lipoprotein metabolism.
Lipoprotein Metabolism
Lipoproteins serve to transport absorbed dietary fat and endogenously synthesized cholesterol and triglyceride. Nevertheless, it is possible to provide a relatively simple overview covering three main areas: the exogenous and endogenous pathways and reverse cholesterol transport. In these various pathways the liver has a pivotal role.
Exogenous Pathway
In the typical Western diet approximately 80-140 G triglyceride and 0.5-1.5 G cholesterol are eaten daily. Following digestion, absorption and reesterification, triglyceride and cholesterol are packaged in the jejunal enterocyte with apoprotein B48 to form chylomicrons.
Chylomicrons
Chylomicrons enter the circulation via intestinal lymphatics and finally the thoracic duct. The large triglyceride component is hydrolysed to fatty acids and glycerol by the lipoprotein lipase enzyme, which is bound to endothelium in capillary beds of muscle and adipose tissue.The hydrolysis of cholomicron triglyceride by lipoprotein lipase enables the delivery of fatty acids either as fuel in muscle or for reesterification to triglyceride and storage in adipose tissue.
In relation to overall cholesterol homeostasis it is important to recognize that the cholesterol component of chylomicrons remains with the particle so that dietary cholesterol is delivered to the liver almost quantitatively.
Endogenous Pathway
Very Low Density Lipoproteins
Triglyceride and cholesterol synthesized in the liver are secreted in very low density lipoprotein (VLDL) particles which serve to transport the lipids to the periphery. VLDL forms a spectrum of particles that differ in size and metabolic fate.
Hepatic Cholesterol Synthesis
This is a highly complex process beginning with acetyl CoA formed from fatty acid oxidation or from carbohydrate breakdown. The rate-determining reaction, which is the conversion of hydroxy methyl glutaryl (HMG) CoA to mevalonate, is catalysed by the enzyme HMG-CoA reductase. It is the activity of this enzyme that largely determines the rate of cholesterol synthesis.
Hepatic Triglyceride Synthesis
Fatty acid flux to the liver from adipose tissue appears to be an important determinant of hepatic triglyceride synthesis and VLDL secretion. Hepatic lipogenesis from carbohydrate substrates is also important.
LDL
LDL is the major cholesterol-rich lipoprotein carrying approximately 70 per cent of plasma cholesterol. It serves to transport cholesterol to peripheral cells.The Nobel laureates Brown and Goldstein identified the LDL receptor that recognizes apoprotein B100 of LDL particles (Brown and Goldstein, 1986). The receptors are large glycoproteins situated on the surface of cells in specialized areas termed coated pits. Coated pits are organelles necessary for the internalization of macromolecules.
The LDL receptor gene has been cloned and localized to the short arm of chromosome 19.The clinical relevance of this structural detail of the receptor will be appreciated when the inborn error of cholesterol metabolism called familial hypercholesterolaemia is discussed. In this condition there are defects in the gene coding for the receptor.
LDL Receptor Pathway
The increasing cellular free cholesterol generated regulates the activities of two enzymes that are of crucial importance in cholesterol homeostasis. HMG-CoA reductase (the major rate- determining enzyme in the cholesterol synthetic pathway) is inhibited, reducing cholesterol synthesis. Acyl CoA: cholesterol acyl transferase (ACAT) is activated, thus facilitating the re-esterification of cholesterol to cholesterol ester. Thus the LDL receptor pathway is a closely integrated system by which cells acquire cholesterol and cellular cholesterol homeostasis is maintained. The therapeutic potential of interrupting this pathway will become apparent when the statin drugs which are inhibitors of HMG-CoA reductase are discussed.It is the activity of LDL receptors in the liver that largely controls plasma LDL levels.Approximately 70 per cent of LDL is removed by this pathway.
High Density Lipoproteins
High density lipoproteins (HDL) are the smallest of the lipoprotein species and transport approximately 20 to 30 per cent of plasma cholesterol. Nascent HDL in the form of bilayer discs containing apoproteins A and phospholipid is secreted by the liver and intestine.Cholesterol ester formed on HDL transfers to other lipoproteins via cholesterol ester transfer protein (CETP) in exchange for triglyceride. Mature HDL consists of two principal subclasses,HDL2 and HDL3.
Reverse Cholesterol Transport
HDL is involved in reverse cholesterol transport whereby cholesterol surplus to cellular requirements is returned from the periphery to the liver for excertion. HDL can act as an acceptor for free cholesterol from tissues. Cholesterol ester transfers from HDL to lipoproteins of lower density such as VLDL and LDL via CETP. Thus the major part of cholesterol ester formed within HDL returns to the liver in other lipoproteins.
Lipids, Lipoproteins and Atherogenesis
LDL cholesterol explains the link between plasma cholesterol, atherosclerosis and CHD. In recent years much has been learned about the interaction of this lipoprotein with cells important in atherogenesis.When experimental animals (including primates) are fed a high-fat, high-cholesterol diet, the first identifiable lesion is the adhesion of monocytes to arterial endothelium.
Modified LDL
In landmark experiments, Goldstein and Brown and colleagues showed that if LDL was chemically modified it was taken up avidly by monocyte/macrophages with foam cell formation (Brown and Goldstein, 1983).Steinberg and colleagues showed that a likely in vivo modification of LDL resulting in uptake by monocyte/macrophages is peroxidation (Steinberg et al., 1989). Indeed oxidatively modified LDL may contribute to atherogenesis in other ways, including direct cytotoxicity to arterial endothelium and the stimulation of monocyte adhesion and moncyte chemotaxis.
LDL Subfractions
LDL is heterogeneous (Krauss and Burke, 1982) and can be separated on density gradient ultracentifugation into subclasses that vary in size, density and lipid content. In healthy subjects the most abundant LDL subclass is LDL-II. Women have proportionately more of the larger, less dense LDL-I particles than men. Conversely, men have proportionately more of the smaller, denser particles give rise to pattern B and larger, less dense particles to pattern A. It is clear from the work of Austin and Krauss and others that LDL pattern B is strongly related to CHD risk (Austin et al., 1988).
HDL and Protection from CHD
HDL cholesterol is inversely related to CHD risk, as discussed in detail in part two. The mechanisms by which increasing HDL concentrations are protective and low levels increase risk remain to be determined. The involvement of HDL in reverse cholesterol transport is an attractive explanation for its protective role.
Triglycerides and Atherogenesis
Triglyceride accumulation is not a feature of the atherosclerotic plaque but triglyceride-rich lipoproteins also contain cholesterol esters and it is likely that some of these are directly atherogenic.
Hypertriglyceridaemia is associated with alterations in the metabolism of other lipoproteins,which may explain its relationship to CHD risk. It is often inversely related to HDL such that as triglycerides increase, HDL cholesterol concentrations decrease.In hypertriglyceridaemic individuals there is a preponderance of small, dense LDL particles. A further explanation for the link between plasma triglyceride and CHD risk relates to the association between hypertriglyceridaemia and coagulation factors. Factor VII is an important component of the extrinsic coagulation system and in prospective studies has been shown to be an independent predictor of CHD. Increasing plasma triglycerides are positively correlated with the activity of factor VII and some of the day-to-day variation in factor VII coagulation activity is related to dietary fat intake.
Plasma triglyceride concentration is also positively correlated with activity of plasminogen activator inhibitor 1 (PAI-1). PAI-1 is an inhibitor of plasminogen activation and has been shown to be increased in young myocardial infarction patients.
Lipoprotein (a)
There is considerable current interest in this lipoprotein, which consists of LDL with an additional apoprotein-apoprotein (a) attached to it via a disulphide bond. Apoprotein (a) has striking structural homology with plasminogen, a zymogen of the coagulation and fibrinolytic system.
Lipoprotein (a) concentrations vary widely within and between populations. In Europeans most individuals have low levels but there is a pronounced positive skew to the distribution with very high levels in some people. The variation appears to be largely determined by the apoprotein (a) gene locus. Plasma concentrations correlate inversely with the molecular mass of apoprotein (a),
which exists in many different size polymorphisms.
The physiology of lipoprotein (a) remains poorly understood but its rate of production appears to be a major determinant of its plasma concentration. It is likely that apoprotein (a) is directly secreted by the liver and then associates with LDL.The importance of lipoprotein (a) relates to its association with CHD risk and, form its structural homology with plasminogen. It is tempting to speculate that this lipoprotein may be an important link with the coagulation system. Many case control studies have demonstrated that high lipoprotein (a) concentrations relate to CHD risk but the association appears to be influenced by the prevailing LDL concentration – the higher the LDL, the stronger the relationship between lipoprotein (a) and CHD.
Cholesterol
In its free, unesterified form cholesterol is a major component (together with phospolipid) of cell membranes. Its presence helps to stabilize membrane fluidity and therefore, the barrier between cell and environment. Cholesterol is also important as a precursor of steroid hormones and of bile acids. Cholesterol present in the plasma and extracellular fluid is largely in the esterified form.
Triglycerides
Triglycerides are produced by the esterification of glycerol with three fatty acid molecules. They are the body’s major energy store, particularly in adipose tissue. Fatty acids are released through the action of hormone-sensitive lipase, an enzyme that becomes active during fasting when insulin levels are low. They can be utilized directly as fuel by muscle or by other tissues,including brain, following partial oxidation to ketone bodies in the liver.
Triglyceride and cholesterol ester are insoluble in the aqueous environment of the plasma and are solubilized by their incorporation into lipoproteins.
Lipoprotein Structure
There are several different lipoprotein species found in plasma but their basic structures are similar. The insoluble lipid (cholesterol ester and triglyceride) forms a central core in the form of a lipid droplet. This is surrounded by an outer monolayer of molecules such as free cholesterol,phospholipids and proteins termed apoproteins, which give the complexes their name. These molecules are able to sit at the water/fat interface because they are partly water-soluble and partly lipid-soluble.
Apoproteins
Apoproteins not only stabilize lipoprotein structure but also have other important regulatory functions in lipoprotein metabolism. Apoproteins B 100 and E are necessary for the binding of lipoproteins to cellular receptors, whereas apoproteins A-I and C-II are activators of enzymes important in lipoprotein metabolism.
Lipoprotein Metabolism
Lipoproteins serve to transport absorbed dietary fat and endogenously synthesized cholesterol and triglyceride. Nevertheless, it is possible to provide a relatively simple overview covering three main areas: the exogenous and endogenous pathways and reverse cholesterol transport. In these various pathways the liver has a pivotal role.
Exogenous Pathway
In the typical Western diet approximately 80-140 G triglyceride and 0.5-1.5 G cholesterol are eaten daily. Following digestion, absorption and reesterification, triglyceride and cholesterol are packaged in the jejunal enterocyte with apoprotein B48 to form chylomicrons.
Chylomicrons
Chylomicrons enter the circulation via intestinal lymphatics and finally the thoracic duct. The large triglyceride component is hydrolysed to fatty acids and glycerol by the lipoprotein lipase enzyme, which is bound to endothelium in capillary beds of muscle and adipose tissue.The hydrolysis of cholomicron triglyceride by lipoprotein lipase enables the delivery of fatty acids either as fuel in muscle or for reesterification to triglyceride and storage in adipose tissue.
In relation to overall cholesterol homeostasis it is important to recognize that the cholesterol component of chylomicrons remains with the particle so that dietary cholesterol is delivered to the liver almost quantitatively.
Endogenous Pathway
Very Low Density Lipoproteins
Triglyceride and cholesterol synthesized in the liver are secreted in very low density lipoprotein (VLDL) particles which serve to transport the lipids to the periphery. VLDL forms a spectrum of particles that differ in size and metabolic fate.
Hepatic Cholesterol Synthesis
This is a highly complex process beginning with acetyl CoA formed from fatty acid oxidation or from carbohydrate breakdown. The rate-determining reaction, which is the conversion of hydroxy methyl glutaryl (HMG) CoA to mevalonate, is catalysed by the enzyme HMG-CoA reductase. It is the activity of this enzyme that largely determines the rate of cholesterol synthesis.
Hepatic Triglyceride Synthesis
Fatty acid flux to the liver from adipose tissue appears to be an important determinant of hepatic triglyceride synthesis and VLDL secretion. Hepatic lipogenesis from carbohydrate substrates is also important.
LDL
LDL is the major cholesterol-rich lipoprotein carrying approximately 70 per cent of plasma cholesterol. It serves to transport cholesterol to peripheral cells.The Nobel laureates Brown and Goldstein identified the LDL receptor that recognizes apoprotein B100 of LDL particles (Brown and Goldstein, 1986). The receptors are large glycoproteins situated on the surface of cells in specialized areas termed coated pits. Coated pits are organelles necessary for the internalization of macromolecules.
The LDL receptor gene has been cloned and localized to the short arm of chromosome 19.The clinical relevance of this structural detail of the receptor will be appreciated when the inborn error of cholesterol metabolism called familial hypercholesterolaemia is discussed. In this condition there are defects in the gene coding for the receptor.
LDL Receptor Pathway
The increasing cellular free cholesterol generated regulates the activities of two enzymes that are of crucial importance in cholesterol homeostasis. HMG-CoA reductase (the major rate- determining enzyme in the cholesterol synthetic pathway) is inhibited, reducing cholesterol synthesis. Acyl CoA: cholesterol acyl transferase (ACAT) is activated, thus facilitating the re-esterification of cholesterol to cholesterol ester. Thus the LDL receptor pathway is a closely integrated system by which cells acquire cholesterol and cellular cholesterol homeostasis is maintained. The therapeutic potential of interrupting this pathway will become apparent when the statin drugs which are inhibitors of HMG-CoA reductase are discussed.It is the activity of LDL receptors in the liver that largely controls plasma LDL levels.Approximately 70 per cent of LDL is removed by this pathway.
High Density Lipoproteins
High density lipoproteins (HDL) are the smallest of the lipoprotein species and transport approximately 20 to 30 per cent of plasma cholesterol. Nascent HDL in the form of bilayer discs containing apoproteins A and phospholipid is secreted by the liver and intestine.Cholesterol ester formed on HDL transfers to other lipoproteins via cholesterol ester transfer protein (CETP) in exchange for triglyceride. Mature HDL consists of two principal subclasses,HDL2 and HDL3.
Reverse Cholesterol Transport
HDL is involved in reverse cholesterol transport whereby cholesterol surplus to cellular requirements is returned from the periphery to the liver for excertion. HDL can act as an acceptor for free cholesterol from tissues. Cholesterol ester transfers from HDL to lipoproteins of lower density such as VLDL and LDL via CETP. Thus the major part of cholesterol ester formed within HDL returns to the liver in other lipoproteins.
Lipids, Lipoproteins and Atherogenesis
LDL cholesterol explains the link between plasma cholesterol, atherosclerosis and CHD. In recent years much has been learned about the interaction of this lipoprotein with cells important in atherogenesis.When experimental animals (including primates) are fed a high-fat, high-cholesterol diet, the first identifiable lesion is the adhesion of monocytes to arterial endothelium.
Modified LDL
In landmark experiments, Goldstein and Brown and colleagues showed that if LDL was chemically modified it was taken up avidly by monocyte/macrophages with foam cell formation (Brown and Goldstein, 1983).Steinberg and colleagues showed that a likely in vivo modification of LDL resulting in uptake by monocyte/macrophages is peroxidation (Steinberg et al., 1989). Indeed oxidatively modified LDL may contribute to atherogenesis in other ways, including direct cytotoxicity to arterial endothelium and the stimulation of monocyte adhesion and moncyte chemotaxis.
LDL Subfractions
LDL is heterogeneous (Krauss and Burke, 1982) and can be separated on density gradient ultracentifugation into subclasses that vary in size, density and lipid content. In healthy subjects the most abundant LDL subclass is LDL-II. Women have proportionately more of the larger, less dense LDL-I particles than men. Conversely, men have proportionately more of the smaller, denser particles give rise to pattern B and larger, less dense particles to pattern A. It is clear from the work of Austin and Krauss and others that LDL pattern B is strongly related to CHD risk (Austin et al., 1988).
HDL and Protection from CHD
HDL cholesterol is inversely related to CHD risk, as discussed in detail in part two. The mechanisms by which increasing HDL concentrations are protective and low levels increase risk remain to be determined. The involvement of HDL in reverse cholesterol transport is an attractive explanation for its protective role.
Triglycerides and Atherogenesis
Triglyceride accumulation is not a feature of the atherosclerotic plaque but triglyceride-rich lipoproteins also contain cholesterol esters and it is likely that some of these are directly atherogenic.
Hypertriglyceridaemia is associated with alterations in the metabolism of other lipoproteins,which may explain its relationship to CHD risk. It is often inversely related to HDL such that as triglycerides increase, HDL cholesterol concentrations decrease.In hypertriglyceridaemic individuals there is a preponderance of small, dense LDL particles. A further explanation for the link between plasma triglyceride and CHD risk relates to the association between hypertriglyceridaemia and coagulation factors. Factor VII is an important component of the extrinsic coagulation system and in prospective studies has been shown to be an independent predictor of CHD. Increasing plasma triglycerides are positively correlated with the activity of factor VII and some of the day-to-day variation in factor VII coagulation activity is related to dietary fat intake.
Plasma triglyceride concentration is also positively correlated with activity of plasminogen activator inhibitor 1 (PAI-1). PAI-1 is an inhibitor of plasminogen activation and has been shown to be increased in young myocardial infarction patients.
Lipoprotein (a)
There is considerable current interest in this lipoprotein, which consists of LDL with an additional apoprotein-apoprotein (a) attached to it via a disulphide bond. Apoprotein (a) has striking structural homology with plasminogen, a zymogen of the coagulation and fibrinolytic system.
Lipoprotein (a) concentrations vary widely within and between populations. In Europeans most individuals have low levels but there is a pronounced positive skew to the distribution with very high levels in some people. The variation appears to be largely determined by the apoprotein (a) gene locus. Plasma concentrations correlate inversely with the molecular mass of apoprotein (a),
which exists in many different size polymorphisms.
The physiology of lipoprotein (a) remains poorly understood but its rate of production appears to be a major determinant of its plasma concentration. It is likely that apoprotein (a) is directly secreted by the liver and then associates with LDL.The importance of lipoprotein (a) relates to its association with CHD risk and, form its structural homology with plasminogen. It is tempting to speculate that this lipoprotein may be an important link with the coagulation system. Many case control studies have demonstrated that high lipoprotein (a) concentrations relate to CHD risk but the association appears to be influenced by the prevailing LDL concentration – the higher the LDL, the stronger the relationship between lipoprotein (a) and CHD.
Hyperlipidemia
Dyslipidemia is an important correctable factor for Coronary Artery Disease. There is a strong, independent, continuous, and graded relation between total cholesterol (TC) or low-density-lipoprotein cholesterol (LDL-C) level and risk for Coronary Artery Disease events. This relation has been clearly demonstrated in men and women and in all age groups. More than one half of U.S. adults (102 million) have TC levels greater than 200 mg/dl, and of these, 40 per cent (41 million) have values greater than 240 mg/dl, and of these, 40 per cent(41 million) have valves greater than 240 mg/dl. In general, a 1 per cent increase in LDL-C level leads to a 2 per cent to 3 per cent increase in risk for Coronary Artery Disease (2).
1) Physiology
a) Lipoproteins are large molecular compounds that are essential to the transport of cholesterol and triglycerides (TGs) within the blood. They contain a lipid core composed of TGs and cholesterol esters surrounded by phospholipids and specialized proteins known as apolipoproteins. The five major families of lipoprotein are chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
b) Apolipoproteins are necessary for the structure and enzymatic processes of lipids.Apolipoprotein A1 (apo A1) is a major component of HDL, and apolipoprotein B (apo B) is the main apolipoprotein for the remaining non-HDL lipoproteins.
2) Lipid-lowering Trials
Aggressive lipid-lowering drug treatment of persons at various risk levels reduces Coronary Artery Disease morbidity and mortality rates and increases overall survival rate. Although the association between hyperlipidemia and Coronary Artery Disease was established much earlier,the demonstration of a reduction in all cause mortality had to await the development of 3-hydroxy-3-methylglutaryl coenzyme a (HMG CoA) reductase inhibitors or statins.
Dyslipidemia is an important correctable factor for Coronary Artery Disease. There is a strong, independent, continuous, and graded relation between total cholesterol (TC) or low-density-lipoprotein cholesterol (LDL-C) level and risk for Coronary Artery Disease events. This relation has been clearly demonstrated in men and women and in all age groups. More than one half of U.S. adults (102 million) have TC levels greater than 200 mg/dl, and of these, 40 per cent (41 million) have values greater than 240 mg/dl, and of these, 40 per cent(41 million) have valves greater than 240 mg/dl. In general, a 1 per cent increase in LDL-C level leads to a 2 per cent to 3 per cent increase in risk for Coronary Artery Disease (2).
1) Physiology
a) Lipoproteins are large molecular compounds that are essential to the transport of cholesterol and triglycerides (TGs) within the blood. They contain a lipid core composed of TGs and cholesterol esters surrounded by phospholipids and specialized proteins known as apolipoproteins. The five major families of lipoprotein are chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
b) Apolipoproteins are necessary for the structure and enzymatic processes of lipids.Apolipoprotein A1 (apo A1) is a major component of HDL, and apolipoprotein B (apo B) is the main apolipoprotein for the remaining non-HDL lipoproteins.
2) Lipid-lowering Trials
Aggressive lipid-lowering drug treatment of persons at various risk levels reduces Coronary Artery Disease morbidity and mortality rates and increases overall survival rate. Although the association between hyperlipidemia and Coronary Artery Disease was established much earlier,the demonstration of a reduction in all cause mortality had to await the development of 3-hydroxy-3-methylglutaryl coenzyme a (HMG CoA) reductase inhibitors or statins.
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