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.
Standard fasting blood tests for cholesterol and lipid profiles will include values for total cholesterol, HDL cholesterol (so-called "good" cholesterol), LDL cholesterol (so-called "bad" cholesterol) and triglycerides. Family history and life style, including factors such as blood pressure and whether or not one smokes, affect what would be considered ideal versus non-ideal values for fasting blood lipid profiles. Included here are the values for various lipids that indicate low to high risk for coronary artery disease.
<200mg/dL = desired values
200 - 239mg/dL = borderline to high risk
240mg/dL and above = high risk
With HDL cholesterol the higher the better.
<40mg/dL for men and <50mg/dL for women = higher risk
40-50mg/dL for men and 50-60mg/dL for woman = normal values
>60mg/dL is associated with some level of protection against heart disease
With LDL cholesterol the lower the better.
<100mg/dL = optimal values
100mg/dL - 129mg/dL = optimal to near optimal
130mg/dL - 159mg/dL = borderline high risk
160mg/dL - 189mg/dL = high risk
190mg/dL and higher = very high risk
With triglycerides the lower the better.
<150mg/dL = normal
150mg/dL - 199mg/dL = borderline to high risk
200mg/dL - 499mg/dL = high risk
>500mg/dL = very high risk
| Apoprotein - MW (Da) | Lipoprotein Association | Function and Comments |
| apoA-I - 29,016 | Chylomicrons, HDL | major protein of HDL, activates lecithin:cholesterol acyltransferase, LCAT |
| apoA-II - 17,400 | Chylomicrons, HDL | primarily in HDL, enhances hepatic lipase activity |
| apoA-IV - 46,000 | Chylomicrons and HDL | present in triacylglycerol rich lipoproteins |
| apoB-48 - 241,000 | Chylomicrons | exclusively 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 - 513,000 | VLDL, IDL and LDL | major protein of LDL, binds to LDL receptor; one of the longest known proteins in humans |
| apoC-I - 7,600 | Chylomicrons, VLDL, IDL and HDL | may also activate LCAT |
| apoC-II - 8, 916 | Chylomicrons, VLDL, IDL and HDL | activates lipoprotein lipase |
| apoC-III - 8,750 | Chylomicrons, VLDL, IDL and HDL | inhibits lipoprotein lipase |
| apoD, 33,000 | HDL | closely associated with LCAT |
| cholesterol ester transfer protein, CETP | HDL | exclusively 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 HDL | binds to LDL receptor, apoEε-4 allele amplification associated with late-onset Alzheimer's disease |
| apoH - 50,000 (also known as β-2-glycoprotein I) | Chylomicrons | triacylglycerol metabolism |
| apo(a) - at least 19 different alleles; protein ranges in size from 300,000 - 800,000 | LDL | disulfide 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 |
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 cholesteryl esters, apoE and apoB-48, are then delivered to, and taken up by, the liver through interaction with the LDL receptor which requires apoE or via the chylomicron remnant receptor, which is a member of the LDL receptor-related protein (LRP) family. The recognition of chylomicron remnants by the hepatic remnant receptor also requires apoE. Chylomicrons function to deliver dietary triacylglycerols to adipose tissue and muscle and dietary cholesterol to the liver.
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.
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.
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.
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 bind to a receptor that is a member of the scavenger receptor family, specifically the scavenger receptor BI: SR-BI (see below). When HDL binds to SR-BI it is not internalized as is the case for LDLs following their binding to the LDL receptor but the cholesteryl esters of HDLs are taken up by the hepatocytes through caveolae while the HDL and SR-BI remain on the plasma membrane. Caveolae (Latin for little caves) are specialized "lipid rafts" present in flask-shaped indentations in the plasma membranes of many cells types that perform a number of signaling functions. Hepatic uptake of HDL-derived cholesterol is referred to as reverse cholesterol transport. Macrophages also bind HDLs through SR-BI interaction. HDLs can then acquire cholesterol and apoE from the macrophages and the cholesterol-enriched HDLs are then released from the macrophages which is another route of reverse cholesterol transport.
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 scavenger receptor pathway, specifically via the B1 scavenger receptor (SR-B1).
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.
The LDL receptor-related protein family represents a group of structurally related transmembrane proteins involved in a diverse range of biological activities including lipid metabolism, nutrient transport, protection against atherosclerosis, as well as numerous developmental processes. The LDL receptor (LDLR) described above represents the founding member of this family of proteins. The LRPs include LRP1, LRP1b, LRP2 (also called megalin), LRP4 (also called MEGF7 for multiple epidermal growth factor-like domains protein 7), LRP5/6, LRP8 (also called apolipoprotein E receptor 2), the VLDL receptor (VLDLR), and LR11/SorLA1 (LDL receptor relative with 11 ligand binding repeats/sorting protein related receptor containing LDLR class A repeats).
LRP1 is also known as CD91 or α2macroglobulin receptor. This receptor is expressed in numerous tissues and is known to be involved in diverse activities that include lipoprotein transport, modulation of platelet derived growth factor receptor-β (PDGFRβ) signaling, regulation of cell-surface protease activity, and the control of cellular entry of bacteria and viruses. Regulation of PDFGRβ activity mediates the protective effects of LRP1 in development of atherosclerosis. LRP1 is synthesized as a 600kDa precursor that is proteolytically processed into a 85kDa transmembrane protein and a 515kDa extracellular protein. The extracellular protein non-covalently associates with the transmembrane protein. LRP1 has been shown to bind more than 40 different ligands that include lipoproteins, extracellular matrix proteins, cytokines and growth factors, protease and protease inhibitor complexes, and viruses. This diverse array of ligands clearly demonstrates that LRP1 is involved in numerous biological and physiological processes.
LRP2 was originally identified as an autoantigen in a rat model of autoimmune kidney disease called Heymann nephritis. LRP2 is expressed in numerous tissues and is found in the apical surfaces of epithelial borders as well as intracellularly in endosomes. In the proximal convoluted tubule of the kidney LRP2 is involved in the reabsorption of numerous molecules. LRP2 binds lipoproteins, hormones, vitamins, vitamin-binding proteins, proteases and, protease inhibitor complexes.
The LRP5/6 proteins serve as co-receptors in Wnt signaling (see the Wnts, TGFs, and BMPs page for more details).
The founding member of the scavenger receptor family was identified in studies that were attempting to determine the mechanism by with LDL accumulated in macrophages in atherosclerotic plaques. Macrophages ingest a variety of negatively charged macromolecules that includes modified LDLs. These studies led to the identification of two types of macrophage scavenger receptors identified as type I and type II. Subsequent research determined that the scavenger receptor family consists of several families of that are identified as class A receptors, class B receptors, mucin-like receptors, and endothelial receptors. After binding ligand the scavenger receptors can either be internalized, similar to the process of internalization of LDL receptors, or they can remain on the cell surface and transfer lipid into the cell through caveolae or they can mediate adhesion.
The class A receptors include the type I and II macrophage scavenger receptors as well as an additional macrophage receptor called MARCO (macrophage receptor with collagenous structure). The class B receptors include CD36 and scavenger receptor class B type I (SR-BI). The mucin-like receptors include CD68/macrosialin and the fruit fly scavenger receptor; dSR-CI. The endothelial receptors bind oxidized LDL and are called the LOX-1 receptors.
The SR-BI protein has been shown to be the endogenous receptor for HDLs in the liver. Additionally, the HDL-SR-BI interaction in the adrenal glands is the mechanism for the delivery of cholesterol to the steroid hormone synthesizing cells of this tissue. HDLs first bind to SR-BI and then the cholesteryl esters present in the HDLs are transferred to the membrane for uptake via caveolae. The importance of the fact that the HDL-SR-BI complex remains at the cell surface is evident from the observation that this ligand-receptor interaction is also involved in the removal of cholesterol from cells by HDLs in the process of reverse cholesterol transport.
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.
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.
Atorvastatin (Lipotor®), Simvastatin (Zocor®), Lovastatin (Mevacor®): These drugs are fungal HMG-CoA reductase (HMGR) inhibitors and are members of the family of drugs referred to as the statins. 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. A component of the natural cholesterol lowering supplement, red yeast rice, is in fact a statin-like compound.
The statins have become recognized as a class of drugs capable of more pharmacologic benefits than just lowering blood cholesterol levels via their actions on HMGR. Part of the cardiac benefit of the statins relates to their ability to regulate the production of S-nitrosylated COX-2. COX-2 is an inducible enzyme involved in the synthesis of the prostaglandins and thromboxanes as well as the lipoxins and resolvins. The latter two classes of compounds are anti-inflammatory lipids discussed in the Aspirin page. Evidence has shown that statins activate inducible nitric oxide synthase (iNOS) leading to nitrosylation of COX-2. The S-nitrosylated COX-2 enzyme produces the lipid compound 15R-hydroxyeicosatetraenoic acid (15R-HETE) which is then converted via the action of 5-lipoxygenase (5-LOX) to the epimeric lipoxin, 15-epi-LXA4. This latter compound is the same as the aspirin-triggered lipoxin (ATL) that results from the aspirin-induced acetylation of COX-2. Therefore, part of the beneficial effects of the statins are exerted via the actions of the lipoxin family of anti-inflammatory lipids.
Additional anti-inflammatory actions of the statins results from a reduction in the prenylation of numerous pro-inflammatory modulators. Prenylation refers to the addition of the 15 carbon farnesyl group or the 20 carbon geranylgeranyl group to acceptor proteins. The isoprenoid groups are attached to cysteine residues at the carboxy terminus of proteins in a thioether linkage (C-S-C). A common consensus sequence at the C-terminus of prenylated proteins has been identified and is composed of CAAX, where C is cysteine, A is any aliphatic amino acid (except alanine) and X is the C-terminal amino acid. In addition to numerous prenylated proteins that contain the CAAX consensus, prenylation is known to occur on proteins of the RAB family of RAS-related G-proteins. There are at least 60 proteins in this family that are prenylated at either a CC or CXC element in their C-termini. The RAB family of proteins are involved in signaling pathways that control intracellular membrane trafficking. The prenylation of proteins allows them to be anchored to cell membranes. In addition to cell membrane attachment, prenylation is known to be important for protein-protein interactions. Thus, inhibition of this post-translational modification by the statins interferes with the important functions of many signaling proteins which is manifest by inhibition of inflammatory responses.
Some of the effects on immune function that have been attributed to the statins are attenuation of autoimmune disease, inhibition of T-cell proliferation, inhibition of inflammatory co-stimulatory molecule expression, decreases in leukocyte infiltration, and promotion of a shift in cytokine profiles of helper T-cell types from Th1 to Th2. Th1 cells are involved in cell-mediated immunity processes, whereas, Th2 cells are involved in humoral immunity process. The cytokines produced by Th2 cells include IL-4, IL-5, IL-10 and IL-13 and these trigger B cells to switch to IgE production and to activate eosinophils.
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. In addition, nicotinic administration strongly increases the circulating levels of HDLs. Patient compliance with nicotinic acid administration is sometimes compromised because of the unpleasant side-effect of flushing (strong cutaneous vasodilation). Recent evidence has shown that nicotinic acid binds to and activates the G-protein coupled receptor identified as GPR109A (also called HM74A or PUMA-G). The identity of a receptor to which nicotinic acid binds allows for the development of new drug therapies that activate the same receptor but that may lack the negative side-effect of flushing associated with nicotinic acid. 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.
Gemfibrozil (Lopid®), Fenofibrate (TriCor®): These compounds (called fibrates) are derivatives of fibric acid and although used clinically since the 1930's were only recently discovered to exert some of their lipid-lowering effects via the activation of peroxisome proliferation. Specifically, the fibrates were found to be activators of the peroxisome proliferator-activated receptor-α (PPAR-α) class of proteins that are classified as co-activators. The naturally occurring ligands for PPAR-α are leukotriene B4 (LTB4, see the Lipid Synthesis page), unsaturated fatty acids and oxidized components of VLDLs and LDLs. The PPARs interact with another receptor family called the retinoid X receptors (RXRs) that bind 9-cis-retinoic acid. Activation of PPARs results in modulation of the expression of genes involved in lipid metabolism. In addition the PPARs modulate carbohydrate metabolism and adipose tissue differentiation. Fibrates result in the activation of PPAR-α in liver and muscle. In the liver this leads to increased β-oxidation of fatty acids, thereby decreasing the liver's secretion of triacylglycerol- and cholesterol-rich VLDLs, as well as increased clearance of chylomicron remnants, increased levels of HDLs and increased lipoprotein lipase activity which in turn promotes rapid VLDL turnover.
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.
Return to The Mobile Medical Biochemistry Page
Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu