3 Биологические мембраны. Обмен веществом (1160072), страница 19
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Nutr. Int. 2, 290-297.We discussed chylomicrons in Chapter 16, in connection with themovement of dietary triacylglycerols from the intestine to other tissues. They are the largest of the lipoproteins and the least dense, containing a high proportion of triacylglycerols (see Fig. 16-2).
Chylomicrons are synthesized in the endoplasmic reticulum of epithelial cellsthat line the small intestine, then move through the lymphatic system,entering the bloodstream through the left subclavian vein. The apolipoproteins of chylomicrons include apoB-48 (unique to this class of lipoproteins), apoE, and apoC-II (Table 20-3). ApoC-II activates lipoprotein lipase in the capillaries of adipose, heart, skeletal muscle, andlactating mammary tissues, allowing the release of free fatty acids tothese tissues. Chylomicrons thus carry fatty acids obtained in the dietto the tissues in which they will be consumed or stored as fuel. Theremnants of chylomicrons, depleted of most of their triacylglycerols butstill containing cholesterol, apoE, and apoB-48, move through thebloodstream to the liver, where they are taken up, degraded in lysosomes, and their constituents recycled.Table 20—3 Apolipoproteins of the human plasma lipoproteinsApolipoproteinMolecularweightLipoproteinassociationApoA-IApoA-IIApoA-IVApoB-48ApoB-100ApoC-IApoC-II28,33117,38044,000240,000513,0007,0008,837HDLHDLChylomicrons, HDLChylomicronsVLDL, LDLVLDL, HDLChylomicrons,VLDL, HDLChylomicrons,VLDL, HDLHDLChylomicrons,VLDL, HDLApoC-IIIApoDApoE8,75132,50034,145Function (if known)Activates LCATBinds to LDL receptorActivates lipoproteinlipaseInhibits lipoproteinlipaseTriggers clearance ofVLDL and chylomicronremnantsSource: Modified from Vance, D.E.
& Vance, J.E. (eds) (1985) Biochemistry of Lipids and Membranes. The Benjamin/Cummings Publishing Company, Menlo Park, CA.Chapter 20 Lipid Biosynthesis677When the diet contains more fatty acids than are needed immediately as fuel, they are converted into triacylglycerols in the liver andpackaged with specific apolipoproteins into very low-density lipoprotein, VLDL.
Excess carbohydrate in the diet can also be convertedinto triacylglycerols in the liver and exported as VLDLs. In addition totriacylglycerols, VLDLs contain some cholesterol and cholesteryl esters, as well as apoB-100, apoC-I, apoC-II, apoC-III, and apo-E (Table20-3).
These lipoproteins are transported in the blood from the liver tomuscle and adipose tissue, where activation of lipoprotein lipase byapoC-II causes the release of free fatty acids from the triacylglycerolsof the VLDL. Adipocytes take up these fatty acids, resynthesize triacylglycerols from them, and store the products in intracellular lipid droplets, whereas myocytes mostly oxidize them to supply energy. MostVLDL remnants are removed from circulation by hepatocytes, via receptor-mediated uptake and lysosomal degradation.The loss of triacylglycerols converts some VLDL to low-densitylipoprotein, LDL (Table 20-2).
Very rich in cholesterol and cholesteryl esters and containing apoB-100 as their major apoprotein, LDLscarry cholesterol to peripheral tissues (in addition to the liver) thathave specific surface receptors that recognize apoB-100. These receptors mediate the uptake of cholesterol and cholesteryl esters in a process described below.The fourth major lipoprotein type, high-density lipoprotein,HDL, begins in the liver and small intestine as small, protein-richparticles containing relatively little cholesterol and no cholesteryl esters. HDLs contain apoC-I and apoC-II, among other apolipoproteins(Table 20-3), as well as the enzyme lecithin-cholesterol acyl transferase (LCAT), which catalyzes the formation of cholesteryl estersfrom lecithin (phosphatidylcholine) and cholesterol (Fig.
20-38). LCATon the surface of nascent (newly forming) HDL particles converts thecholesterol and phosphatidylcholine of chylomicron and VLDL remOII1CH2—O—C—R1Figure 20-38 The reaction catalyzed by lecithincholesterol acyl transferase (LCAT). This enzyme ispresent on the surface of HDL and is stimulated bythe HDL component apoA-I. The cholesteryl estersaccumulate within nascent HDLs, converting themto mature HDLs.OCH—O—C—R2+OCH2-O-P-O-CH2-CH2—N(CH3)3HOO"Phosphatidylcholine (lecithin)Cholesterollecithin-cholesterolacyl transferase(LCAT)oCH2-O-C-R1CH—OHOCH 2 -O-P-O-CH 2 —CH 2 -N(CH 3 ) 3IO"Lysolecithin,R2—CoCholesteryl ester678Part III Bioenergetics and Metabolismnants to cholesteryl esters, which begin to form a core, transformingthe disc-shaped nascent HDL to a mature, spherical HDL particle.This cholesterol-rich lipoprotein now returns to the liver, where thecholesterol is unloaded. Some of this cholesterol is converted into bilesalts.Cholesteryl Esters Enter Cells byReceptor-Mediated EndocytosisFigure 20-39 Uptake of cholesterol by receptormediated endocytosis.
Endocytosis is also describedin Chapter 2 (p. 32).Each LDL particle circulating in the bloodstream contains apoB-100,which as noted above is recognized by specific surface receptor proteins, LDL receptors, on cells that need to take up cholesterol. Thebinding of LDL to an LDL receptor initiates endocytosis (see Fig. 2 10), which brings the LDL and its associated receptor into the cellwithin an endosome (Fig. 20-39).
This endosome eventually fuses witha lysosome, which contains enzymes that hydrolyze the cholesteryl es-LDL particleApoB-100Cholesteryl esterKJnI Receptor-mediated %&I endocytosis% EndosomeEndoplasmicreticulumCholesterolLysosomeCholesterylester dropletFattyacidsAminoacidsChapter 20 Lipid Biosynthesis679ters, releasing cholesterol and fatty acid into the cytosol. The apoB-100of LDL is also degraded to amino acids, which are released to the cytosol, but the LDL receptor escapes degradation and returns to the cellsurface, where it can again function in LDL uptake. This pathway forthe transport of cholesterol in blood and its receptor-mediated endocytosis by target tissues was elucidated by Michael Brown and Joseph Goldstein.Cholesterol entering cells by this path may be incorporated intomembranes or may be reesterified by ACAT (Fig.
20—36) for storagewithin cytosolic lipid droplets. The accumulation of excess intracellular cholesterol is prevented by reducing the rate of cholesterol synthesis when sufficient cholesterol is available from LDL in the blood.Cholesterol Biosynthesis Is Regulated by Several FactorsCholesterol synthesis is a complex and energy-expensive process, andit is clearly advantageous to an organism to be able to regulate thesynthesis of cholesterol so as to complement the intake of cholesterol inthe diet.
In mammals, cholesterol production is regulated by intracellular cholesterol concentration and by the hormones glucagon andinsulin. The rate-limiting step in the pathway to cholesterol isthe conversion of /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) intomevalonate (Fig. 20-32), and the enzyme that catalyzes this reaction,HMG-CoA reductase, is a complex regulatory enzyme whose activity ismodulated over a 100-fold range. It is allosterically inhibited by as yetunidentified derivatives of cholesterol and of the key intermediatemevalonate (Fig. 20-40). HMG-CoA reductase is also hormonally regulated.
The enzyme exists in phosphorylated (inactive) and dephosphorylated (active) forms. Glucagon stimulates phosphorylation (inactivation), and insulin promotes dephosphorylation, activating the enzymeand favoring cholesterol synthesis.In addition to its immediate inhibition of existing HMG-CoA reductase, high intracellular cholesterol also slows the synthesis of new molecules of the enzyme. Furthermore, high intracellular concentrationsof cholesterol also activate ACAT (Fig. 20-40), increasing esterificationof cholesterol for storage. Finally, high intracellular cholesterol causesreduced production of the LDL receptor, slowing the uptake of cholesterol from the blood.Unregulated cholesterol production can lead to serious disease.When the sum of the cholesterol synthesized and obtained in the dietexceeds the amount required for the synthesis of membranes, bilesalts, and steroids, pathological accumulations of cholesterol in bloodvessels (atherosclerotic plaques) can develop in humans, resulting inobstruction of blood vessels (atherosclerosis).
Heart failure from occluded coronary arteries is a leading cause of death in industrializedsocieties. Atherosclerosis is linked to high levels of cholesterol in theblood, and particularly to high levels of LDL-bound cholesterol; thereis a negative correlation between HDL levels and arterial disease.In the human genetic disease known as familial hypercholesterolemia, blood levels of cholesterol are extremely high, and afflicted individuals develop severe atherosclerosis in childhood. The LDL receptoris defective in these individuals, and the receptor-mediated uptake ofcholesterol carried by LDL does not occur.
Consequently, cholesterolobtained in the diet is not cleared from the blood; it accumulates andcontributes to the formation of atherosclerotic plaques. EndogenousMichael Brown and Joseph GoldsteinAcetyl-CoA/3-Hydroxy-/3-methylglutaryl-CoA- insulinHMC-CuA- glucagonMevalonate,Cholesterylestersc^ACATCholesterol .•(intracellular)receptormediatedendocytosisLDL-cholesterol(extracellular)Figure 20-40 Regulation of cholesterol biosynthesis balances synthesis with dietary uptake. Glucagon acts by promoting phosphorylation of HMGCoA reductase, insulin by promoting dephosphorylation. X represents unidentified metabolites ofcholesterol and mevalonate, or other unidentifiedsecond messengers.Part III Bioenergetics and Metabolism680cholesterol synthesis continues even in the presence of excessive cholesterol in the blood, because the extracellular cholesterol cannot enterthe cytosol to regulate intracellular synthesis.
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