Interrelationship of Triglycerides with Lipoproteins and High-Density Lipoproteins Antonio M. Gotto, Jr., MD, DPhil Triglycerides are transported by the largest and most lipid-rich of the lipoproteln particles, namely, chylomicrons and very low density lipoproteins (VLDL). These particles are buoyant because of the high triglyceride content, which makes up approximately 90% by weight of the chylomicron and 70% by weight of the VLDL. The chytomicron transports exogenous or dletary fat and cholesterol, whereas VLDL transports endogenous triglyceride and cholesterol in lipoproteins synthesized and secreted by the liver. Both chylomicrons and VLDL are hydrolyzed at the capillary surface by the enzyme lipoprotein lipase. Lipoprotein lipase catalyzes the hydrolysis of triglyceride in the lipid core of these particles, producing smaller particles known as remnants. We currently believe the remnants are atherogenic and that this is one reason why hypertriglyceridemia may predispose to coronary artery disease. Chylomicron remnants are recognized and removed by hepatic receptors that contain apolipoprotein (apo) E. The rate of clearance of remnant particles depends on which subfraction of apo E is present. Particles containing apo Eli are removed more slowly than those with apo Elll and EIV. The dietary cholesterol from the chylomicron remnant particles is thought to down-regulate the hepatic low-density lipoprotein (LDL) receptors. VLDL remnants, also called intermediate-density lipoprotein (IDL), contain apo E and may be removed by the liver through the LDL or B/E receptor. The decrease in activity of these receptors results in apparent oversynthesis of LDL, the end-product of VLDL and IDL metabolism. LDL is the major cholesterol carrier, followed by high-density lipoprotein (HDL). LDL carries approximately up to three-fourths of the cholesterol in the blood, and about two-thirds of LDL is removed by specific LDL receptors as it circulates. The other portion is removed by low-affinity pathways. HDL contains approximately 50% cholesterol and phospholipid. HDL is synthesized in the liver, the Intestine and also originates from the surface of chylomicrons and VLDL during lipolysis. HDL acquires cholesterol from peripheral tissues and is esFrom the Department of Medicine, Baylor College of Medicine and the Internal Medicine Service, The Methodist Hospital, Houston, Texas. Address for reprints: Antonio M. Gotto, Jr., MD, DPhil, Department of Internal Medicine, The Methodist Hospital, 6565 Fannin, A601, Houston, Texas 77030.
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
terified by the lecithin cholesterol acyltransferase or LCAT to cholesteryl ester. The cholesteryl ester may then be transferred from HDL to LDL, IDL or VLDL by the cholesteryl ester transfer protein. lhus, cholesterol can be transported to the liver indirectly by HDL, and HDL fractions containing apo E may directly transport HDL to the liver. HDL exists in a nascent form before being converted into spherical particles. There is some evidence that apo Al may play a particularly important role in this reverse cholesterol transport process. HDL may be subdivided in several ways: one based on its apoprotein content and one based on its density (e.g., HDLz and HDL3). In hypertriglyceridemia, the formation of HDL from the hydrolysis of triglyceride-rich particles may be diminished. In addition, when postprandial lipemia occurs, or when there is a prolonged elevation of triglyceride-&h lipoproteins, an increased transfer of trfglyceride from triglyceride-rich lipoprotein particles into LDL and HDL may occur in exchange for cholesteryl ester. The metabolic changes associated with hypertriglyceridemia may decrease the concentration of HDL and result in small, dense particles of LDL and HDL. (Am J Cardiol 1990$&2OA43A)
ipoproteins transport lipids in 3 separate ways: the exogenouspathway, the endogenouspathway and the reversecholesterolpathway. We will focus on the first 2 of theseroutes, by which cholesteroland the triglyceride-rich lipoproteins (chylomicrons and very low density lipoproteins [VLDL] are metabolized.’ Exogenous pathway: Dietary cholesterolis absorbed into the intestinal wall and packagedinto particles called chylomicrons. Apolipoprotein (apo) B48, a truncated form of the apo BlOO made in the liver, is incorporated into the chylomicrons. Two other apos-apo E and CIIare added to the chylomicrons either in the lymph or after these particles reach the circulation. Apo CII is required for activation of the enzyme lipoprotein lipase (LPL), which catalyzestriglyceride hydrolysis in the lipid core of the chylomicron and results in smaller particles known as chylomicron remnants. Apo E is required for recognition of these remnants by the hepatic receptors. There are 2 ways in which triglycerides interact with high-density lipoprotein (HDL): First, the cholesterylester and triglycerides are exchangedbetweenthe chylomicron remnant and HDL (Fig. 1). LPL is attached to receptorson the surface of capillary endothelial cells; the
L
Lipoprotein
lipase low
FIGURE 1. The interaction between trigiycetideo and high-density lipoprotein (HDL) choksterol in the presence of lipoprotein lipase. CE = cholesterol ester; PL = phospholipase; pp =postprandial; TG = triglycceride.
Gut
higher the concentration of LPL, the more rapidly these chylomicron particles are removed from the blood. Second, as the chylomicrons are broken down and the triglycerides are attacked by LPL, surface components from the chylomicron particles are transferred to and incorporated into HDL, increasing the mass of the HDL particle. The concentration of LPL correlates positively with the concentrations of HDL and its subfraction HDL?.’ When LPL activity is increased, chylomicron particles will be cleared from the circulation more rapidly, so that endothelial cells will not be exposed to these particles. Several factors can influence the activity of LPL. Exercise increases LPL activity, whereas cigarette smoking has the opposite effect. The affinity of this enzyme for the chylomicron particle also appears to be increased by estrogen. Finally, LPL activity is insulin-dependent. As triglycerides are being hydrolyzed from the core of the chylomicron and the surface components are being transferred to HDL, the now smaller chylomicron remnant remains to carry dietary cholesterol to the liver. Apo E on the remnant surface is then recognized by hepatic apo E receptors, so that the particles will be removed from the circulation and taken up by the liver cells. The rate of clearance depends on the subfraction of apo E present (i.e., particles containing apo EIV are removed more quickly than those containing apo EII). This uptake and removal process is significant in that it is believed to increase the cholesterol level within the liver, thus downregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the amount of circulating LDL cholesterol. Endogenous pathway: Lipoprotein transport begins with the synthesis of VLDL by the liver. VLDL, which contains apo BlOO, CII and E, is also converted by LPL to a smaller particle or remnant, called intermediatedensity lipoprotein (IDL). As IDL is converted to LDL,
apo C and E are transferred to HDL. These remnants (about 40% of VLDL) can be removed directly by the hepatic LDL-receptors through apo E binding, whereas LDL is removed by LDL-receptors binding to apo BlOO. About two-thirds of the LDL is believed to be removed by this mechanism; the other one-third is taken up by peripheral tissues involving so-called low-affinity pathways. Observations in an animal model (Watanabe rabbits) of familial hypercholesterolemia suggest that oxidized LDL is more rapidly taken up by these low-affinity or macrophage receptors in the arterial intima and thus contributes to the development of atherosclerotic plaque.’ In the process of converting the triglyceride-rich lipoproteins (the chylomicrons and VLDL) to chylomicron remnants and IDL or LDL, respectively, the apos become the key determinants of the structure and density of each particle. Apos are lost from the surface of lipoprotein particles and, along with cholesterol and phospholipid, are transferred to HDL. In the end, LDL contains only 1 large apo, BlOO, which directs it to the B/E or LDL receptor.” LDL levels can be increased owing to deficiencies or abnormalities of the B/E receptor. There are at least 4 different sources of HDL (Fig. 2): (1) the chylomicrons and VLDL, which may be considered together; (2) the intestine, which secretes the apos associated with phospholipid that constitute a nascent form of HDL; (3) the liver, which also secretes a nascent form of HDL; (4) the macrophages within the arterial wall, which can secrete an apo E and phospholipid particle that may serve as another nascent form of HDL. Thus, if one inhibits LPL activity or interferes with the breakdown of triglyceride-rich lipoproteins, HDL mass will be decreased and there will be less HDL in the blood. Nascent HDL particles can take up cholesterol from the peripheral tissues, after which the enzyme lecithin cholesterol acyltransferase, or LCAT, converts the cho-
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER4, 1990
2iA
A SYMPOSIUM:
HDL CHOLESTEROL
IN CORONARY
ARTERY
DISEASE
Lipids Apolipoproteins
Phospholipids
Choleste
FIGURE 2. Origin of highdensity lipoprotein (HDL) chek&erol. There are at least 4 different sources: (1) the chylamlls (Chylos) and very low density lipoprotein (VLDL), (2) the intestine, (3) the liver, and (4) arterial wall macrophages. CE = chdaded ester; LCAT = lecithin cho&storol acyllranderase.
E
z2oo:/2
TABLE
I Perspective from Framingham
Patients with high TG levels may be at high risk for CHD Patients with very low TG/HDL cholesterol ratios are an exception -10% of these patients have a low (
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 66
terified by the lecithin cholesterol acyltransferase or LCAT to cholesteryl ester. The cholesteryl ester may then be transferred from HDL to LDL, IDL or VLDL by the cholesteryl ester transfer protein. lhus, cholesterol can be transported to the liver indirectly by HDL, and HDL fractions containing apo E may directly transport HDL to the liver. HDL exists in a nascent form before being converted into spherical particles. There is some evidence that apo Al may play a particularly important role in this reverse cholesterol transport process. HDL may be subdivided in several ways: one based on its apoprotein content and one based on its density (e.g., HDLz and HDL3). In hypertriglyceridemia, the formation of HDL from the hydrolysis of triglyceride-rich particles may be diminished. In addition, when postprandial lipemia occurs, or when there is a prolonged elevation of triglyceride-&h lipoproteins, an increased transfer of trfglyceride from triglyceride-rich lipoprotein particles into LDL and HDL may occur in exchange for cholesteryl ester. The metabolic changes associated with hypertriglyceridemia may decrease the concentration of HDL and result in small, dense particles of LDL and HDL. (Am J Cardiol 1990$&2OA43A)
ipoproteins transport lipids in 3 separate ways: the exogenouspathway, the endogenouspathway and the reversecholesterolpathway. We will focus on the first 2 of theseroutes, by which cholesteroland the triglyceride-rich lipoproteins (chylomicrons and very low density lipoproteins [VLDL] are metabolized.’ Exogenous pathway: Dietary cholesterolis absorbed into the intestinal wall and packagedinto particles called chylomicrons. Apolipoprotein (apo) B48, a truncated form of the apo BlOO made in the liver, is incorporated into the chylomicrons. Two other apos-apo E and CIIare added to the chylomicrons either in the lymph or after these particles reach the circulation. Apo CII is required for activation of the enzyme lipoprotein lipase (LPL), which catalyzestriglyceride hydrolysis in the lipid core of the chylomicron and results in smaller particles known as chylomicron remnants. Apo E is required for recognition of these remnants by the hepatic receptors. There are 2 ways in which triglycerides interact with high-density lipoprotein (HDL): First, the cholesterylester and triglycerides are exchangedbetweenthe chylomicron remnant and HDL (Fig. 1). LPL is attached to receptorson the surface of capillary endothelial cells; the
L
Lipoprotein
lipase low
FIGURE 1. The interaction between trigiycetideo and high-density lipoprotein (HDL) choksterol in the presence of lipoprotein lipase. CE = cholesterol ester; PL = phospholipase; pp =postprandial; TG = triglycceride.
Gut
higher the concentration of LPL, the more rapidly these chylomicron particles are removed from the blood. Second, as the chylomicrons are broken down and the triglycerides are attacked by LPL, surface components from the chylomicron particles are transferred to and incorporated into HDL, increasing the mass of the HDL particle. The concentration of LPL correlates positively with the concentrations of HDL and its subfraction HDL?.’ When LPL activity is increased, chylomicron particles will be cleared from the circulation more rapidly, so that endothelial cells will not be exposed to these particles. Several factors can influence the activity of LPL. Exercise increases LPL activity, whereas cigarette smoking has the opposite effect. The affinity of this enzyme for the chylomicron particle also appears to be increased by estrogen. Finally, LPL activity is insulin-dependent. As triglycerides are being hydrolyzed from the core of the chylomicron and the surface components are being transferred to HDL, the now smaller chylomicron remnant remains to carry dietary cholesterol to the liver. Apo E on the remnant surface is then recognized by hepatic apo E receptors, so that the particles will be removed from the circulation and taken up by the liver cells. The rate of clearance depends on the subfraction of apo E present (i.e., particles containing apo EIV are removed more quickly than those containing apo EII). This uptake and removal process is significant in that it is believed to increase the cholesterol level within the liver, thus downregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the amount of circulating LDL cholesterol. Endogenous pathway: Lipoprotein transport begins with the synthesis of VLDL by the liver. VLDL, which contains apo BlOO, CII and E, is also converted by LPL to a smaller particle or remnant, called intermediatedensity lipoprotein (IDL). As IDL is converted to LDL,
apo C and E are transferred to HDL. These remnants (about 40% of VLDL) can be removed directly by the hepatic LDL-receptors through apo E binding, whereas LDL is removed by LDL-receptors binding to apo BlOO. About two-thirds of the LDL is believed to be removed by this mechanism; the other one-third is taken up by peripheral tissues involving so-called low-affinity pathways. Observations in an animal model (Watanabe rabbits) of familial hypercholesterolemia suggest that oxidized LDL is more rapidly taken up by these low-affinity or macrophage receptors in the arterial intima and thus contributes to the development of atherosclerotic plaque.’ In the process of converting the triglyceride-rich lipoproteins (the chylomicrons and VLDL) to chylomicron remnants and IDL or LDL, respectively, the apos become the key determinants of the structure and density of each particle. Apos are lost from the surface of lipoprotein particles and, along with cholesterol and phospholipid, are transferred to HDL. In the end, LDL contains only 1 large apo, BlOO, which directs it to the B/E or LDL receptor.” LDL levels can be increased owing to deficiencies or abnormalities of the B/E receptor. There are at least 4 different sources of HDL (Fig. 2): (1) the chylomicrons and VLDL, which may be considered together; (2) the intestine, which secretes the apos associated with phospholipid that constitute a nascent form of HDL; (3) the liver, which also secretes a nascent form of HDL; (4) the macrophages within the arterial wall, which can secrete an apo E and phospholipid particle that may serve as another nascent form of HDL. Thus, if one inhibits LPL activity or interferes with the breakdown of triglyceride-rich lipoproteins, HDL mass will be decreased and there will be less HDL in the blood. Nascent HDL particles can take up cholesterol from the peripheral tissues, after which the enzyme lecithin cholesterol acyltransferase, or LCAT, converts the cho-
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER4, 1990
2iA
A SYMPOSIUM:
HDL CHOLESTEROL
IN CORONARY
ARTERY
DISEASE
Lipids Apolipoproteins
Phospholipids
Choleste
FIGURE 2. Origin of highdensity lipoprotein (HDL) chek&erol. There are at least 4 different sources: (1) the chylamlls (Chylos) and very low density lipoprotein (VLDL), (2) the intestine, (3) the liver, and (4) arterial wall macrophages. CE = chdaded ester; LCAT = lecithin cho&storol acyllranderase.
E
z2oo:/2
TABLE
I Perspective from Framingham
Patients with high TG levels may be at high risk for CHD Patients with very low TG/HDL cholesterol ratios are an exception -10% of these patients have a low (
