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Intestinal Uptake of Lipids
In order for the body to make use of dietary lipids, they must first be absorbed from the small intestine. Since these molecules are oils, they are essentially insoluble in the aqueous environment of the intestine. The solubilization (or emulsification) of dietary lipids is thereforeaccomplished by means of bile salts, which are synthesized from cholesterol in the liver and then stored in the gallbladder; they are secreted following the ingestion of fat.
The emulsification of dietary fats renders them accessible to pancreatic lipases (primarily lipase and phospholipase A2). These enzymes, secreted into the intestine from the pancreas, generate free fatty acids and a mixtures of mono- and diacylglycerols from dietary triacylglycerols. Pancreatic lipase degrades triacylglycerols at the 1 and 3 positions sequentially to generate 1,2-diacylglycerols and 2-acylglycerols. Phospholipids are degraded at the 2 position by pancreatic phospholipase A2 releasing a free fatty acid and the lysophospholipid. The products of pancreatic lipases then diffuse into the intestinal epithelial cells, where the re-synthesis of triacyglycerols occurs.
Dietary triacylglycerols and cholesterol, as well as triacylglycerols and cholesterol synthesized by the liver, are solubilized in lipid-protein complexes. These complexes contain triacylglycerol lipid droplets and cholesteryl esters surrounded by the polar phospholipids and proteins identified as apolipoproteins. These lipid-protein complexes vary in their content of lipid and protein.
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Composition of the Major Lipoprotein Complexes
ComplexSourceDensity (g/ml)%Protein%TGa%PLb%CEc%Cd%FFAe
*HDL2Intestine, liver (chylomicrons and VLDLs) 1.063-1.12533-355-1532-4320-305-100
*HDL3Intestine, liver (chylomicrons and VLDLs) 1.125-1.2155-573-1326-4615-302-66
Albumin-FFAAdipose tissue>1.281990000100
aTriacylglycerols, bPhospholipids, cCholesteryl esters, dFree cholesterol, eFree fatty acids
*HDL2 and HDL3 derived from nascent HDL as a result of the acquisition of cholesteryl esters
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Apoprotein Classifications
Apoprotein - MW (Da)Lipoprotein AssociationFunction and Comments
apoA-I - 29,016Chylomicrons, HDLmajor protein of HDL, activates lecithin:cholesterol acyltransferase, LCAT
apoA-II - 17,400Chylomicrons, HDLprimarily in HDL, enhances hepatic lipase activity
apoA-IV - 46,000Chylomicrons and HDLpresent in triacylglycerol rich lipoproteins
apoB-48 - 241,000Chylomicronsexclusively found in chylomicrons, derived from apoB-100 gene by RNA editing in intestinal epithelium; lacks the LDL receptor-binding domain of apoB-100
apoB-100 - 513,000VLDL, IDL and LDLmajor protein of LDL, binds to LDL receptor; one of the longest known proteins in humans
apoC-I - 7,600Chylomicrons, VLDL, IDL and HDLmay also activate LCAT
apoC-II - 8, 916Chylomicrons, VLDL, IDL and HDLactivates lipoprotein lipase
apoC-III - 8,750Chylomicrons, VLDL, IDL and HDLinhibits lipoprotein lipase
apoD, 33,000HDLclosely associated with LCAT
cholesterol ester transfer protein, CETPHDLexclusively associated with HDL, cholesteryl ester transfer
apoE - 34,000 (at least 3 alleles [E2, E3, E4] each of which have multiple isoforms)Chylomicron remnants, VLDL, IDL and HDLbinds to LDL receptor, apoEe-4 allele amplification associated with late-onset Alzheimer's disease
apoH - 50,000 (also known as b-2-glycoprotein I) Chylomicronstriacylglycerol metabolism
apo(a) - at least 19 different alleles; protein ranges in size from 300,000 - 800,000LDLdisulfide bonded to apoB-100, forms a complex with LDL identified as lipoprotein(a), Lp(a); strongly resembles plasminogen; may deliver cholesterol to sites of vascular injury, high risk association with premature coronary artery disease and stroke
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Chylomicrons are assembled in the intestinal mucosa as a means to transport dietary cholesterol and triacylglycerols to the rest of the body. Chylomicrons are, therefore, the molecules formed to mobilize dietary (exogenous) lipids. The predominant lipids of chylomicrons are triacylglycerols (see Table above). The apolipoproteins that predominate before the chylomicrons enter the circulation include apoB-48 and apoA-I, -A-II and IV. ApoB-48 combines only with chylomicrons.
Chylomicrons leave the intestine via the lymphatic system and enter the circulation at the left subclavian vein. In the bloodstream, chylomicrons acquire apoC-II and apoE from plasma HDLs. In the capillaries of adipose tissue and muscle, the fatty acids of chylomicrons are removed from the triacylglycerols by the action of lipoprotein lipase (LPL), which is found on the surface of the endothelial cells of the capillaries. The apoC-II in the chylomicrons activates LPL in the presence of phospholipid. The free fatty acids are then absorbed by the tissues and the glycerol backbone of the triacylglycerols is returned, via the blood, to the liver and kidneys. Glycerol is converted to the glycolytic intermediate dihydroxyacetone phosphate (DHAP). During the removal of fatty acids, a substantial portion of phospholipid, apoA and apoC is transferred to HDLs. The loss of apoC-II prevents LPL from further degrading the chylomicron remnants.
Chylomicron remnants--- containing primarily cholesterol, apoE and apoB-48--- are then delivered to, and taken up by, the liver through interaction with the chylomicron remnant receptor. The recognition of chylomicron remnants by the hepatic remnant receptor requires apoE. Chylomicrons function to deliver dietary triacylglycerols to adipose tissue and muscle and dietary cholesterol to the liver.
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Very Low Density Lipoproteins, LDLs
The dietary intake of both fat and carbohydrate, in excess of the needs of the body, leads to their conversion into triacylglycerols in the liver. These triacylglycerols are packaged into VLDLs and released into the circulation for delivery to the various tissues (primarily muscle and adipose tissue) for storage or production of energy through oxidation. VLDLs are, therefore, the molecules formed to transport endogenously derived triacylglycerols to extra-hepatic tissues. In addition to triacylglycerols, VLDLs contain some cholesterol and cholesteryl esters and the apoproteins, apoB-100, apoC-I, apoC-II, apoC-III and apoE. Like nascent chylomicrons, newly released VLDLs acquire apoCs and apoE from circulating HDLs.
The fatty acid portion of VLDLs is released to adipose tissue and muscle in the same way as for chylomicrons, through the action of lipoprotein lipase. The action of lipoprotein lipase coupled to a loss of certain apoproteins (the apoCs) converts VLDLs to intermediate density lipoproteins (IDLs), also termed VLDL remnants. The apoCs are transferred to HDLs. The predominant remaining proteins are apoB-100 and apoE. Further loss of triacylglycerols converts IDLs to LDLs.
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Intermediate Density Lipoproteins, IDLs
IDLs are formed as triacylglycerols are removed from VLDLs. The fate of IDLs is either conversion to LDLs or direct uptake by the liver. Conversion of IDLs to LDLs occurs as more triacylglycerols are removed. The liver takes up IDLs after they have interacted with the LDL receptor to form a complex, which is endocytosed by the cell. For LDL receptors in the liver to recognize IDLs requires the presence of both apoB-100 and apoE (the LDL receptor is also called the apoB-100/apoE receptor). The importance of apoE in cholesterol uptake by LDL receptors has been demonstrated in transgenic mice lacking functional apoE genes. These mice develop severe atherosclerotic lesions at 10 weeks of age.
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Low Density Lipoproteins, LDLs
The cellular requirement for cholesterol as a membrane component is satisfied in one of two ways: either it is synthesized de novo within the cell, or it is supplied from extra-cellular sources, namely, chylomicrons and LDLs. As indicated above, the dietary cholesterol that goes into chylomicrons is supplied to the liver by the interaction of chylomicron remnants with the remnant receptor. In addition, cholesterol synthesized by the liver can be transported to extra-hepatic tissues if packaged in VLDLs. In the circulation VLDLs are converted to LDLs through the action of lipoprotein lipase. LDLs are the primary plasma carriers of cholesterol for delivery to all tissues.
The exclusive apolipoprotein of LDLs is apoB-100. LDLs are taken up by cells via LDL receptor-mediated endocytosis, as described above for IDL uptake. The uptake of LDLs occurs predominantly in liver (75%), adrenals and adipose tissue. As with IDLs, the interaction of LDLs with LDL receptors requires the presence of apoB-100. The endocytosed membrane vesicles (endosomes) fuse with lysosomes, in which the apoproteins are degraded and the cholesterol esters are hydrolyzed to yield free cholesterol. The cholesterol is then incorporated into the plasma membranes as necessary. Excess intracellular cholesterol is re-esterified by acyl-CoA-cholesterol acyltransferase (ACAT), for intracellular storage. The activity of ACAT is enhanced by the presence of intracellular cholesterol.
Insulin and tri-iodothyronine (T3) increase the binding of LDLs to liver cells, whereas glucocorticoids (e.g., dexamethasone) have the opposite effect. The precise mechanism for these effects is unclear but may be mediated through the regulation of apoB degradation. The effects of insulin and T3 on hepatic LDL binding may explain the hypercholesterolemia and increased risk of athersclerosis that have been shown to be associated with uncontrolled diabetes or hypothyroidism.
An abnormal form of LDL, identified as lipoprotein-X (Lp-X), predominates in the circulation of patients suffering from lecithin-cholesterol acyl transferase (LCAT, see HDL discussion for LCAT function) deficiency or cholestatic liver disease. In both cases there is an elevation in the level of circulating free cholesterol and phospholipids.
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High Density Lipoproteins, HDLs
HDLs are synthesized de novo in the liver and small intestine, as primarily protein-rich disc-shaped particles. These newly formed HDLs are nearly devoid of any cholesterol and cholesteryl esters. The primary apoproteins of HDLs are apoA-I, apoC-I, apoC-II and apoE. In fact, a major function of HDLs is to act as circulating stores of apoC-I, apoC-II and apoE.
HDLs are converted into spherical lipoprotein particles through the accumulation of cholesteryl esters. This accumulation converts nascent HDLs to HDL2 and HDL3. Any free cholesterol present in chylomicron remnants and VLDL remnants (IDLs) can be esterified through the action of the HDL-associated enzyme, lecithin:cholesterol acyltransferase, LCAT. LCAT is synthesized in the liver and so named because it transfers a fatty acid from the C-2 position of lecithin to the C-3-OH of cholesterol, generating a cholesteryl ester and lysolecithin. The activity of LCAT requires interaction with apoA-I, which is found on the surface of HDLs.
Cholesterol-rich HDLs return to the liver, where they are endocytosed. Hepatic uptake of HDLs, or reverse cholesterol transport, may be mediated through an HDL-specific apoA-I receptor or through lipid-lipid interactions. Macrophages also take up HDLs through apoA-I receptor interaction. HDLs can then acquire cholesterol and apoE from the macrophages; cholesterol-enriched HDLs are then secreted from the macrophages. The added apoE in these HDLs leads to an increase in their uptake and catabolism by the liver.
HDLs also acquire cholesterol by extracting it from cell surface membranes. This process has the effect of lowering the level of intracellular cholesterol, since the cholesterol stored within cells as cholesteryl esters will be mobilized to replace the cholesterol removed from the plasma membrane.
The cholesterol esters of HDLs can also be transferred to VLDLs and LDLs through the action of the HDL-associated enzyme, cholesterol ester transfer protein (CETP). This has the added effect of allowing the excess cellular cholesterol to be returned to the liver through the LDL-receptor pathway as well as the HDL-receptor pathway.
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LDL Receptors
LDLs are the principal plasma carriers of cholesterol delivering cholesterol from the liver (via hepatic synthesis of VLDLs) to peripheral tissues, primarily the adrenals and adipose tissue. LDLs also return cholesterol to the liver. The cellular uptake of cholesterol from LDLs occurs following the interaction of LDLs with the LDL receptor (also called the apoB-100/apoE receptor). The sole apoprotein present in LDLs is apoB-100, which is required for interaction with the LDL receptor.
The LDL receptor is a polypeptide of 839 amino acids that spans the plasma membrane. An extracellular domain is responsible for apoB-100/apoE binding. The intracellular domain is responsible for the clustering of LDL receptors into regions of the plasma membrane termed coated pits. Once LDL binds the receptor, the complexes are rapidly internalized (endocytosed). ATP-dependent proton pumps lower the pH in the endosomes, which results in dissociation of the LDL from the receptor. The portion of the endosomal membranes harboring the receptor are then recycled to the plasma membrane and the LDL-containing endosomes fuse with lysosomes. Acid hydrolases of the lysosomes degrade the apoproteins and release free fatty acids and cholesterol. As indicated above, the free cholesterol is either incorporated into plasma membranes or esterified (by ACAT) and stored within the cell.
The level of intracellular cholesterol is regulated through cholesterol-induced suppression of LDL receptor synthesis and cholesterol-induced inhibition of cholesterol synthesis. The increased level of intracellular cholesterol that results from LDL uptake has the additional effect of activating ACAT, thereby allowing the storage of excess cholesterol within cells. However, the effect of cholesterol-induced suppression of LDL receptor synthesis is a decrease in the rate at which LDLs and IDLs are removed from the serum. This can lead to excess circulating levels of cholesterol and cholesteryl esters when the dietary intake of fat and cholesterol exceeds the needs of the body. The excess cholesterol tends to be deposited in the skin, tendons and (more gravely) within the arteries, leading to atherosclerosis.
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Clinical Significances of Lipoprotein Metabolism
Fortunately, few individuals carry the inherited defects in lipoprotein metabolism that lead to hyper- or hypolipoproteinemias (see Tables below for brief descriptions). Persons suffering from diabetes mellitus, hypothyroidism and kidney disease often exhibit abnormal lipoprotein metabolism as a result of secondary effects of their disorders. For example, because lipoprotein lipase (LPL) synthesis is regulated by insulin, LPL deficiencies leading to Type I hyperlipoproteinemia may occur as a secondary outcome of diabetes mellitus. Additionally, insulin and thyroid hormones positively affect hepatic LDL-receptor interactions; therefore, the hypercholesterolemia and increased risk of athersclerosis associated with uncontrolled diabetes or hypothyroidism is likely due to decreased hepatic LDL uptake and metabolism.
Of the many disorders of lipoprotein metabolism, familial hypercholesterolemia (FH) may be the most prevalent in the general population. Heterozygosity at the FH locus occurs in 1:500 individuals, whereas, homozygosity is observed in 1:1,000,000 individuals. FH is an inherited disorder comprising four different classes of mutation in the LDL receptor gene. The class 1 defect (the most common) results in a complete loss of receptor synthesis. The class 2 defect results in the synthesis of a receptor protein that is not properly processed in the Golgi apparatus and therefore is not transported to the plasma membrane. The class 3 defect results in an LDL receptor that is incapable of binding LDLs. The class 4 defect results in receptors that bind LDLs but do not cluster in coated pits and are, therefore, not internalized.
FH sufferers may be either heterozygous or homologous for a particular mutation in the receptor gene. Homozygotes exhibit grossly elevated serum cholesterol (primarily in LDLs). The elevated levels of LDLs result in their phagocytosis by macrophages. These lipid-laden phagocytic cells tend to deposit within the skin and tendons, leading to xanthomas. A greater complication results from cholesterol deposition within the arteries, leading to atherosclerosis, the major contributing factor of nearly all cardiovascular diseases.
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Type I (familial LPL deficiency, familial hyperchylomicronemia)(a) deficiency of LPL;
(b) production of abnormal LPL;
(c) apoC-II deficiency
slow chylomicron clearance, reduced LDL and HDL levels; treated by low fat/complex carbohydrate diet; no increased risk of coronary artery disease
Type II (familial hypercholesterolemia, FH)4 classes of LDL receptor defectreduced LDL clearance leads to hypercholesterolemia, resulting in athersclerosis and coronary artery disease
Type III (familial dysbetalipoproteinemia, remnant removal disease, broad beta disease, apolipoprotein E deficiency)hepatic remnant clearance impaired due to apoE abnormality; patients only express the apoE2 isoform that interacts poorly with the apoE receptorcauses xanthomas, hypercholesterolemia and athersclerosis in peripheral and coronary arteries due to elevated levels of chylomicrons and VLDLs
Type IV
(familial hypertriacylglycerolemia)
elevated production of VLDL associated with glucose intolerance and hyperinsulinemiafrequently associated with type-II non-insulin dependent diabetes mellitus, obesity, alcoholism or administration of progestational hormones; elevated cholesterol as a result of increased VLDLs
Type V familialelevated chylomicrons and VLDLs due to unknown causehypertriacylglycerolemia and hypercholesterolemia with decreased LDLs and HDLs
Familial hyperalphalipoproteinemiaincreased level of HDLsa rare condition that is beneficial for health and longevity
Type II
Familial hyperbetalipoproteinemia
increased LDL production and delayed clearance of triacylglycerols and fatty acidsstrongly associated with increased risk of coronary artery disease
Familial ligand-defective apoB2 different mutations: Gln for Arg (amino acid 3500) or Cys for Arg (amino acid 3531); both lead to reduced affinity of LDL for LDL receptordramatic increase in LDL levels; no affect on HDL, VLDL or plasma triglyceride levels; significant cause of hypercholesterolemia and premature coronary artery disease
Familial LCAT deficiencyabsence of LCAT leads to inability of HDLs to take up cholesterol
(reverse cholesterol transport)
decreased levels of plasma cholesteryl esters and lysolecithin; abnormal LDLs (Lp-X) and VLDLs; symptoms also found associated with cholestasis
Wolman's disease
(cholesteryl ester storage disease)
defect in lysosomal cholesteryl ester hydrolase; affects metabolism of LDLsreduced LDL clearance leads to hypercholesterolemia, resulting in athersclerosis and coronary artery disease
heparin-releasable hepatic triglyceride lipase deficiencydeficiency of the lipase leads to accumulation of triacylglycerol-rich HDLs and VLDL remnants (IDLs)causes xanthomas and coronary artery disease

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Abetalipoproteinemia (acanthocytosis, Bassen-Kornzweig syndrome)no chylomicrons, VLDLs or LDLs due to defect in apoB expressionrare defect; intestine and liver accumulate, malabsorption of fat, retinitis pigmentosa, ataxic neuropathic disease, erythrocytes have thorny appearance
Familial hypobetalipoproteinemiaat least 20 different apoB gene mutations identified, LDL concentrations 10-20% of normal, VLDL slightly lower, HDL normalmild or no pathological changes
Familial alpha-lipoprotein deficiency (Tangier disease, Fish-eye disease, apoA-I and -C-III deficiencies)all of these related syndromes have reduced HDL concentrations, no effect on chylomicron or VLDL productiontendency to hypertriacylglycerolemia; some elevation in VLDLs; Fish-eye disease characterized by severe corneal opacity

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Pharmacologic Intervention
Drug treatment to lower plasma lipoproteins and/or cholesterol is primarily aimed at reducing the risk of athersclerosis and subsequent coronary artery disease that exists in patients with elevated circulating lipids. Drug therapy usually is considered as an option only if non-pharmacologic interventions (altered diet and exercise) have failed to lower plasma lipids
  • Mevinolin, Mevastatin, Lovastatin: These drugs are fungal HMG-CoA reductase inhibitors. The net result of treatment is an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-CoA reductase reaction) is required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments carry some risk of toxicity.
  • Nicotinic acid: Nicotinic acid reduces the plasma levels of both VLDLs and LDLs by inhibiting hepatic VLDL secretion, as well as suppressing the flux of FFA release from adipose tissue by inhibiting lipolysis. Because of its ability to cause large reductions in circulating levels of cholesterol, nicotinic acid is used to treat Type II, III, IV and V hyperlipoproteinemias.
  • Clofibrate, Gemfibrozil, Fenofibrate: These compounds are derivatives of fibric acid and promote rapid VLDL turnover by activating lipoprotein lipase. They also induce the diversion of hepatic free fatty acids from esterification reactions to those of oxidation, thereby decreasing the liver's secretion of triacylglycerol- and cholesterol-rich VLDLs.
  • Probucol: Probucol increases the rate of LDL metabolism and may block the intestinal transport of cholesterol. The net result is a significant reduction in plasma cholesterol levels.
  • Cholestyramine or colestipol (resins): These compounds are nonabsorbable resins that bind bile acids which are then not reabsorbed by the liver but excreted. The drop in hepatic reabsorption of bile acids releases a feedback inhibitory mechanism that had been inhibiting bile acid synthesis. As a result, a greater amount of cholesterol is converted to bile acids to maintain a steady level in circulation. Additionally, the synthesis of LDL receptors increases to allow increased cholesterol uptake for bile acid synthesis, and the overall effect is a reduction in plasma cholesterol. (This treatment is ineffective in homozygous FH patients, since they are completely deficient in LDL receptors.
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This article has been modified by Dr. M. Javed Abbas.
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