The common phospholipids in plasma are derived from glycerol and consist of triacylglycerol containing phosphate and a nitrogenous base (glyceropho-spholipids). The phosphate group is usually attached at position 3 of the glycerol molecule, and the nitrogenous base is usually an amino acid or an alcohol. The phosphatidyl cholines (lecithins) are the most common phospholipid and are found in plasma and in cell membranes. Lecithin-cholesterol acyl trans-ferase (LCAT) catalyzes the transfer of a fatty acyl group at position 2 on glycerol to cholesterol to produce cholesteryl ester and leaves monoacyl gly-cerophosphate (lysolecithin). Another class of phos-pholipids, the cephalins, includes phosphatidyl ethanolamine, phosphatidyl serine, and phosphati-dyl inositol.

Phospholipids are able to bridge nonpolar lipids and water and act to allow lipids to mix with water in an emulsion. The nonpolar hydrocarbon end of the phospholipid is attracted to lipid, whereas the polar phosphate group is attracted to water. In a lipid droplet, the inner oily centre is surrounded by phospholipid, which has its outer phosphate group attracted to the surrounding water environment, to form a micelle.

Apolipoproteins A, B, C, and E

The lipoprotein particle (VLDL, LDL, and HDL) is composed of lipid and protein molecules. Among the protein molecules are a group of proteins found at the surface of the lipoprotein particle called apolipoproteins. Their function is integral to the metabolism of lipoproteins. They interact with phos-pholipids to solubilize cholesterol esters and triacyl-glycerol, regulate the reaction of enzymes (LCAT, lipoprotein lipase, and hepatic lipase) with lipid, and bind with cell surface receptors to determine the metabolism of lipoproteins.

Apolipoprotein A This is the main protein of HDL and has two forms, apoA-I and apoA-II. ApoA-I is the main protein component in HDL, and the production and catabolism of apoA-I determine the plasma concentration of HDL cholesterol. It acts as an activator of LCAT, which is responsible for ester-ification of free cholesterol in plasma, and allows the binding of HDL to many cell surfaces. ApoA-II is a structural component of HDL.

Apolipoprotein A-I Milano ApoA-I Milano is a specific form of apoA-I seen in some Italian families, which appears to protect against the development of atherosclerosis.

Apolipoprotein B ApoB-100 is the main protein component of LDL and is synthesized in the liver. It is also found in chylomicrons and VLDL. ApoB-48 is synthesized from the intestine and is the amino-terminal half of apoB-100 synthesized from the same gene. ApoB-100 is the receptor ligand for the LDL receptor.

Apolipoprotein C ApoC is composed of three separate apolipoproteins. ApoC-I is mainly found in VLDL but also in chylomicrons and HDL. ApoC-II is present in a circulating reservoir of HDL, transferring to chylomicrons and VLDL, where it acts as an activator of lipoprotein lipase, allowing the lipo-lysis of triacylglycerols from circulating triacylgly-cerol-rich lipoproteins. ApoC-III is the most abundant form of apoC and may act as a modulator of lipoprotein lipase.

Apolipoprotein E ApoE is a glycoprotein with several isoforms designated as apoE-2, -E-3, and -E-4. ApoE-3 is the most common isoform. It is present in VLDL, IDL, and HDL (mainly HDL2). ApoE facilitates chylomicron remnant metabolism through the chylomicron remnant and VLDL receptors of the liver. ApoE-3 and -E-4 bind avidly with hepatic receptors, whereas apoE-2 is poorly bound. Patients with only apoE-2 isoform clear chylomicron remnants and IDL slowly, and apoE-2 is associated with dysbetalipoproteinemia (type III hyperlipopro-teinemia). ApoE also facilitates metabolism through the LDL receptor (particularly the apoE-4 isoform). A large number of tissues express mRNA for apoE, including the brain, although the reason for this is unclear.

Apolipoprotein (a) Apo(a) joined together with one LDL particle, which contains apoB, constitutes a lipoprotein called Lp(a). Interest in Lp(a) arose because apo(a) shows close sequence homology with plasminogen, suggesting that a high level of Lp(a) would impair thrombolysis. Lp(a) is an independent risk factor for developing vascular disease, with levels above a cutoff value of 300 mg/l placing individuals at risk, especially if combined with other risk factors.


The main function of the lipoproteins is to transport lipids from one organ to another. Their main characteristics are shown in Table 1.

Chylomicrons These are the largest lipoproteins, consisting mainly of triacylglycerol with apoB-48 and apoA, -C, and -E. Triacylglycerol is hydrolyzed with endothelial-bound lipoprotein lipase, changing the chylomicron into a chylomicron remnant rich in cholesteryl ester. These remnants are removed from the circulation by interaction with the remnant receptors mainly present on hepatocytes. Peak chy-lomicronemia occurs 3-6 h after a meal, with a halflife of less than 1 h, and is cleared from the circulation after a 12-h fast.

Very low-density lipoproteins These triacylgly-cerol-rich lipoproteins are secreted mainly by the liver, with apoB-100 and apoE on their surface, whereas some VLDLs are synthesized by the gut. They are transformed into mature VLDLs by accumulating cholesterol ester, apoC, and apoE from HDLs. They then either interact with lipoprotein lipase to convert into IDLs, which can be taken up by the liver, or convert to LDLs by interacting with hepatic triglyceride lipase.

VLDL particles vary in size. Small VLDL is converted into LDL, via IDL, to a greater extent than large VLDL, which is converted to a form of IDL that appears to be removed from the plasma before conversion to LDL.

Intermediate-density lipoproteins IDLs are intermediate particles formed from the conversion of VLDL to LDL. Also known as VLDL remnants, some are removed directly from plasma, whereas some convert into LDL.

Low-density lipoproteins LDL is the major cholesterol-carrying particle in the plasma. The core is cholesterol ester and has one apolipoprotein, apoB-100, per LDL particle. There are different sizes of LDL. Approximately one-third of the intravascular pool is catabolized per day and three-fourths of the circulating LDL is cleared through the liver, mainly through the LDL receptor. Small, dense LDL is more common in some dyslipidemias and may be more easily oxidized than larger LDL. Normal LDL does not cause foam cell formation, but lipid peroxidation of LDL makes the LDL a ligand for certain receptors (the scavenger receptor and perhaps a specific receptor for oxidized LDL) and results in the formation of cholesterol-laden foam cells. In addition, oxidized LDL in the cell wall stimulates the production of cytokines and growth factors, resulting in monocyte recruitment and the proliferation of smooth muscle cells. This mechanism underlies one model of atherogenesis.

High-density lipoproteins Nascent HDL is secreted by the liver and gut. It acquires unesterified cholesterol in the circulation, catalysed by LCAT to cho-lesteryl ester. HDL can pass cholesteryl ester to VLDL in exchange for triacylglycerol, facilitated by cholesterol ester transfer protein (CETP), or HDL can be taken up by the liver directly. The idea that HDL protects against coronary heart disease (CHD) comes from epidemiological studies. A 0.026 mmol/l increase in plasma HDL cholesterol decreases CHD risk by 2% in men and 3% in women.

Enzymes and Transfer Proteins

Acylcoenzyme A Cholesterol acyltransferase (ACAT; EC ACAT-1 and ACAT-2 are membrane-bound proteins responsible for cholesterol ester formation, metabolizing excess cholesterol within cells to cholesterol ester, which is allosterically activated by cholesterol.

Adenosine-binding cassette transporter In peripheral tissues, adenosine-binding cassette transporter (ABCA-1) protein facilitates transfer of intracellular cholesterol out of cells to lipid-poor apoA-1 or pre-^ HDL particles. When it is deficient or inactive, cholesterol accumulates in peripheral tissues as in Tangier disease or familial HDL deficiency.

Cholesterol Ester transfer protein CETP mediates the exchange of cholesteryl ester from HDL with triacylglycerol from VLDL or chylomicrons.

Fatty acid binding protein Fatty acid binding proteins (FABPs) play a role in the solubilization of long-chain fatty acids (LCFAs) and their CoA-esters to various intracellular organelles. FABPs serve as intracellular receptors of LCFAs and are involved in ligand-dependent transactivation of peroxisome pro-liferator-activated receptors (PPARs) in trafficking LCFAs to the nucleus.

Hepatic lipase (EC Hepatic lipase (HL) is an endothelial-bound enzyme that removes triacyl-glycerol from lipoproteins in the metabolism of chy-lomicrons, VLDL, and HDL. HL hydrolyzes HDL triacylglycerol and phospholipids to form HDL3 from HDL2, contributing to the process of HDL regeneration in the reverse cholesterol transfer process.

Lecithin-cholesterol acyltransferase (EC

LCAT mediates the esterification of cholesterol by transferring a fatty acid from lecithin to cholesterol to form cholesteryl ester.

Lipoprotein lipase (EC Lipoprotein lipase and hepatic lipase are endothelial-bound enzymes that remove triacylglycerol from lipopro-teins. Lipoprotein lipase is activated by apoC-II and is involved in catabolism of chylomicrons and VLDL. Endothelial lipase, lipoprotein lipase, and hepatic lipase belong to the same gene family.

Microsomal triglyceride transfer protein Microsomal triglyceride transfer protein is present in enterocytes and hepatocytes, and it is responsible for adding neutral lipid to apoB to protect it from ubiquitiny-lation and degradation.

Phospholipid transfer protein Phospholipid transfer protein transfers phospholipids from other lipo-proteins to HDL, contributing to the functionality of HDL.

Sterol regulatory element binding protein SREBP is a protein that binds with part of the LDL receptor promoter to increase cholesterol synthesis.


A large number of lipoprotein receptors have been identified. Some of the more important receptors are discussed here. Lipoprotein uptake at the cell membrane may be non-receptor-mediated, perhaps by pinocytosis, where 'binding' is of low affinity but is not saturable.

LDL receptor The LDL receptor (LDLR) is a transmembrane glycoprotein present on most cell surfaces, encoded on chromosome 19. Free cholesterol, building up in the cell through the receptor, reduces both cell synthesis of cholesterol and cell uptake of more LDL cholesterol.

LDL receptor-related protein The LDL receptor-related protein (LRP) is a multifunctional receptor (binding VLDL/chylomicron remnants and other nonlipid ligands such as bacterial toxins) present in nearly all tissues. It has a high affinity for apoE and a low affinity for apoB-100.

VLDL receptor This receptor binds VLDL, ,3-VLDL, and IDL. It recognizes apoE and is located mainly in adipose tissue and muscle.

Scavenger receptors These receptors are found on macrophages and hepatic endothelium. They bind and degrade chemically modified LDL, such as oxidized or acetylated LDL. They are not downreg-ulated by intracellular cholesterol accumulation. Hepatocellular uptake of HDL and/or its cholesteryl ester content is facilitated by a scavenger receptor and a HDL receptor.

Other remnant receptors The lipolysis-stimulated receptor found on fibroblasts recognizes surface apoE and takes up VLDL, chylomicrons, and LDL. Two membrane-binding proteins (MBP 200 and MBP 235) have been described on macrophages and appear to bind VLDL. Remnants from both chylomicrons and VLDL (after hydrolysis of more than 70% of their triacylglycerol content) appear to be removed by both the LDL and the LRP receptors.

Peroxisome proliferator-activated receptors PPARs are a family of intranuclear receptors, including PPARa and PPAR6, that regulate a variety of genes involved in lipid metabolism, thrombosis, and inflammation.

Exogenous (Dietary) Lipid Pathways

Ingestion of food containing fat (triacylglycerol) and cholesterol results in absorption into the enterocyte of fatty acids, monoacylglycerols, free cholesterol, and lysolecithin. In the enterocyte, reesterification of fatty acids into triacylglycerol and cholesterol into cholesteryl ester occurs to form chylomicrons, to which is added a surface layer of apoB-48, -A-I, -A-II, and -A-IV, phospholipid, and free cholesterol. This allows secretion of the chylomicron into the intestinal lymphatics. ApoB-48 is required for secretion of the chylomicron. ApoB-48 is a truncated form of apoB-100, synthesized in the liver but missing the LDL receptor-binding domain of apoB-100. The action of the apoB-editing enzyme in entero-cytes changes a nucleotide base in apoB mRNA to a stop codon. There is one apoB-48 per intestinal triglyceride-rich particle.

Chylomicrons in the circulation take up apoC from HDL (releasing it back to HDL later) and acquire apoE. ApoC-II allows the chylomicron to activate lipoprotein lipase on capillary endothelial cells of muscle and fat. This allows hydrolysis of triacylglycerol, releasing glycerol and fatty acids to be taken up by local tissue. Surface phospholipids, free cholesterol, and apoC transfer to HDL as the particle shrinks. This small chylomicron is called a chylomicron remnant and is catabolized through the LDL receptor and other remnant receptors on the liver. This transport of dietary lipid from the intestinal to the peripheral tissues is shown in Figure 3.

Endogenous Lipid Pathways

The liver is the main source of endogenous lipid (Figure 4). In particular, the liver secretes the tria-cylglycerol-rich lipoprotein VLDL. Triacylglycerol, which is formed from fatty acids either newly synthesised or taken up from plasma, together with free cholesterol, synthesised from acetate or delivered to the liver in chylomicron remnants, join with apoB and phospholipids to form VLDL. ApoC and apoE are added in the circulation. Triacylglycerol is progressively removed from VLDL in the same way as occurs with chylomicrons. Free cholesterol transfers to HDL and is esterified with LCAT and transferred back to VLDL, using a protein called cholesteryl ester transfer protein (CETP), in exchange for triacylglycerol transfer from VLDL to HDL. In this way, VLDL becomes smaller and transforms to become IDL, although some small VLDLs may be removed directly. IDL is further changed through interaction with hepatic lipase to LDL. In this way, most VLDL is transformed to LDL.

Reverse Cholesterol Transport

Lipids are transported to the peripheries from the gut and the liver. They return to the liver via HDL in a process known as reverse cholesterol transport (Figure 5). HDL particles arise in the liver and gut from a coalescence of apoA-I and phospholipid to

Dietary cholesterol and triacylglycerol

Dietary cholesterol and triacylglycerol

Figure 3 Exogenous (dietary) lipid pathway. This shows the transport of dietary lipid from intestine to peripheral tissues and liver. Movement of apolipoprotein between high-density lipoprotein (HDL) and chylomicrons is shown. LRP, low-density lipoprotein (LDL) receptor-related protein.


Figure 4 Endogenous lipid pathway. This shows the formation of very low-density lipoprotein (VLDL) lipid particles (VLDL-i and VLDL2) in the liver with the interconversion, through the action of lipoprotein lipase, to VLDL remnant and through immediate-density lipoprotein (IDL) to LDL. Lipids are taken up from LDL both peripherally and in the liver. LRP, low-density lipoprotein receptor-related protein.

Figure 4 Endogenous lipid pathway. This shows the formation of very low-density lipoprotein (VLDL) lipid particles (VLDL-i and VLDL2) in the liver with the interconversion, through the action of lipoprotein lipase, to VLDL remnant and through immediate-density lipoprotein (IDL) to LDL. Lipids are taken up from LDL both peripherally and in the liver. LRP, low-density lipoprotein receptor-related protein.



and bile acids

Figure 5 Reverse cholesterol transport. Nascent high-density lipoprotein (HDL3) picks up free cholesterol from the peripheries to become HDL2, by a lecithin-cholesterol acyl transferase (LCAT)-mediated conversion. Cholesterol is then transported to the liver with uptake by the SRBI receptor. A second method of transport to the liver involves CETP-mediated esterification of HDL and conversion into immediate-density lipoprotein (IDL) and low-density lipoprotein (LDL), which is then taken up by the LDL receptor. This transfer of lipid between HDL2 and VLDL/IDL maintains a cycle within HDL, and IDL/LDL deliver cholesterol from the peripheries to the liver. HDL may also deliver cholesterol directly to the liver. FC, free cholesterol.

and bile acids

Figure 5 Reverse cholesterol transport. Nascent high-density lipoprotein (HDL3) picks up free cholesterol from the peripheries to become HDL2, by a lecithin-cholesterol acyl transferase (LCAT)-mediated conversion. Cholesterol is then transported to the liver with uptake by the SRBI receptor. A second method of transport to the liver involves CETP-mediated esterification of HDL and conversion into immediate-density lipoprotein (IDL) and low-density lipoprotein (LDL), which is then taken up by the LDL receptor. This transfer of lipid between HDL2 and VLDL/IDL maintains a cycle within HDL, and IDL/LDL deliver cholesterol from the peripheries to the liver. HDL may also deliver cholesterol directly to the liver. FC, free cholesterol.

form cholesterol-deficient bilayered discs in the form of HDL3. Circulating HDL particles, particularly a subset of HDL3 called pre-^ HDL or lipid-poor apoA-I, come into contact with cells, and ABCA-1 acts to move free cholesterol from the cell surface and out of the cells. This cholesterol is converted by LCAT to cholesteryl ester and moves into the core of the HDL, forming mature cholesterol-rich HDL. After accumulating cholesterol, the HDL starts to accept other apolipoproteins and becomes HDL2. In turn, HDL2 appears to pass cholesteryl ester to triglyceride-rich lipoproteins such as chylomicrons, chylomicron remnants, and VLDL under the influence of CETP. The cholesterol then finds its way back to the liver in the form of chylomicron remnants, IDL, and LDL. Some of the HDL2 particles may lose cholesterol directly to the liver and some may be taken up directly by the liver.

Consequences of Hyperlipidemia

Clear evidence exists that as serum cholesterol rises, the risk of CHD rises, and as serum cholesterol falls, the risk of developing CHD falls. The epidemiologi-cal evidence comes from within-country studies, between-country studies, and migration studies. Support comes from animal studies and there is evidence of the beneficial effects of reducing serum cholesterol in both primary and secondary prevention of ischemic heart disease.

The within-country studies include the Multiple Risk Factor Trial Intervention (MRFIT) study, which followed 360 000 middle-aged men screened and followed up for CHD mortality. MRFIT showed a strong positive correlation between cholesterol levels at initial screening and later death from CHD. The Framingham Heart Study, started in 1949, is another prospective survey that followed a large cohort of Americans and examined lipid levels and risk of CHD, particularly the relationships between lipoprotein fractions and CHD. It showed a strong association between elevated LDL cholesterol and increased incidence of CHD and an inverse association between HDL cholesterol and CHD risk. Framingham has drawn attention to the value of the ratio of total cholesterol to HDL cholesterol, where a ratio of 3 or less suggests the disease is static and a ratio of 4 or higher suggests the disease is progressive. Framingham also drew attention to the incremental effect of additional risk factors in the development of CHD, such as hypertension, hyperglycemia, and smoking. Combinations of risk factors occur in the metabolic syndrome, in which insulin resistance appears to be the common denominator.

The best known between-country study is the Seven Countries Study by Ancel Keys linking diet, hypercholesterolemia, and CHD. He showed that a plot of each country's median total cholesterol against deaths from CHD was highly correlated. The variations in serum cholesterol were highly correlated with the ratio of saturated to unsaturated fats in the diet.

Studies of migration and CHD include the Ni-Hon-San Study, in which cholesterol levels and CHD rates were compared in Japanese living in Japan, Honolulu, and San Francisco. There was a rise in both cholesterol levels and CHD rates across these groups, suggesting that as Japanese adopted a Western lifestyle their cholesterol increased and their risk of CHD increased.

Evidence that treatment of hyperlipidemia influences CHD is substantial. The methods of treating hyperlipidemia have varied from diet to drugs, surgery, meditation, and multiple risk factor reduction. The conclusion is that treatment of hyperlipidemia improves CHD morbidity and mortality. The Lipid Research Clinics Coronary Primary Prevention Trial, started in the 1970s, examined 4000 men without evidence of CHD but with hypercholester-olemia, randomized to receive cholestyramine or placebo. After 7 years, despite a relatively minor difference in cholesterol levels, there was a 20% decrease in CHD in the drug-treated group.

In the Oslo study, high-risk Norwegian men were given antismoking and dietary advice, resulting in a significant reduction in the incidence of CHD. The effect of partial ileal bypass surgery has been studied in patients who had experienced a myocardial infarction and were hypercholesterolemic (POSCH study). This surgical procedure improved blood lipids and reduced morbidity caused by CHD. In the Scandinavian Simvastatin Survival Study (4S study), patients with CHD and hypercholesterolemia were randomized to receive the HMG-CoA reductase inhibitor simvastatin or placebo. After a 4-year follow-up period, both morbidity and mortality were significantly reduced in the treatment group. This secondary prevention study was followed by a primary prevention study using pravastatin in men with hypercholester-olemia. This study (WOSCOPS study) randomized men without evidence of CHD to treatment with the HMG-CoA reductase inhibitor pravastatin or to placebo and followed them for 4.9 years. Treatment with the drug significantly reduced the incidence of myocardial infarction and death from cardiovascular causes. In the Air Force/Texas Coronary Atherosclerosis Prevention Study, a primary prevention study, subjects with low levels of LDL cholesterol and HDL cholesterol showed a reduced risk of CHD with statins. The Helsinki Heart Study and the Veterans Affairs-HDL Intervention Study used fibrate drugs in patients with low LDL cholesterol and showed impressive increases in HDL cholesterol and reductions in CHD risk. A 1% increase in HDL was equivalent to a 3% decrease in CHD risk.

Studies such as the Cholesterol Lowering Atherosclerosis Study, in which patients were allocated to drug therapy or placebo, used coronary angiography to follow the effect of drugs on disease. A small reduction in cholesterol results in a disproportionately larger reduction in cardiovascular events.

These studies show that it is possible to arrest progress of the disease and, in some cases, bring about regression of atherosclerosis. The extent to which this happens seems to depend on the underlying disease and the degree of cholesterol lowering.

Atherosclerosis has a complex and multifactorial etiology characterized by inflammation. Clinical markers of inflammation include C-reactive protein, modified LDL, homocysteine, lipoprotein (a), and fibrinogen, which are emerging risk factors and may give prognostic information for patient management. Folate may be beneficial by reducing plasma homocysteine, enhancing endothelial nitric oxide, and showing antiinflammatory properties. Other antiinflammatory agents, such as IL-10, may be of benefit.

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