Class Note for BIOC 460 at UA
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Date Created: 02/06/15
Biochemistry 460 Dr Tischler LIPID TRANSPORT Related Reading Chapter 22 619620 Chapter 26 745748 in Stryer 639h edition OBJECTIVES 1 Describe the ve steps of digestion and absorption of lipids including the important enzymes and location where each step occurs 2 Describe the general structure of a lipoprotein 3 Name the 4 main classes of lipoproteins and the major lipid components and apoproteins of each including the function of the apoprotein Describe the lipidtransport functions of each lipoprotein Discuss the function oflipoprotein lipase Compare and contrast the steps in the processing of chylomicrons and of VLDL Describe how defects in the LDL receptor are associated with familial hypercholesterolemia and atherosclerosis 3995 PHYSIOLOGICAL PREMISE Atherosclerosis is a major cause of death in this country Excess cholesterol in the blood accumulates on the walls of blood vessels which provide oxygen to the heart This accumulation causes the formation of plaques As the plaque increases in size it occludes the blood vessel reducing oxygen delivery to the affected part of the heart Eventually no oxygen is delivered to the cells making them ischemic The ischemia causes cells to die resulting potentially in a myocardial infarction In bypass surgery blood vessels obtained from extremities are attached to quotbypassquot the area of occluded blood vessel LIPID DIGESTION AND ABSORPTION Dietary Lipids saturated fatty acid CH3CH2nCOOH unsaturated fatty acid CH3CHCHCH2nCOOH polyunsaturated fatty acid CH3CHCHCH2CHCHCH2nCOOH X CH2OOCR1 CHZOH HOOCRl X l l RzCOOnCH CHOH HOOCRz l X l CH2OOCR3 CHZOH HOOCR3 Triacylglycerol Glycerol Fatty acids Figure 1 General structures of fatty acids and triacylglycerol Lipolysis of stored triacylglycerol by lipases produces fatty acids plus glycerol can occur in intestinal lumen fat cells muscle liver and kidney Lipid Transport 1 On average fat lipid makes up 37 of the calories in the American diet Fat is energy rich and provides 9 kcalgm Dietary lipids are primarily 90 triacylglycerols Fig l but also include cholesterol esters phospholipids essential unsaturated fatty acids and fat soluble vitamins A D E K In normal individuals essentially all 98 of the fat consumed in the diet is absorbed and most is transported to adipose for storage Triacylglycerols in the diet are hydrolyzed in the intestine by lipases released from the pancreas but are then reassembled in the intestinal cells The poor water solubility of lipids presents problems for digestion because the substrates are not easily accessible to the digestive enzymes in the aqueous phase and the lipolytic products tend to aggregate to larger complexes that make poor contact with the cell surface and therefore are not easily absorbed This latter problem is overcome by quotsolubilizationquot of the lipid products with bile acids Aside from the solubility aspects the general principle ofalietary lipid assimilation is that ofhyalrolyzing large non absorbable molecules into smaller units Dietary fats are transported to tissues as triacylglycerol or cholesterol via chylomicrons On arrival at peripheral tissues eg adipose or muscle the fatty acids are removed from the triacylglycerol by a lipase lipoprotein lipase located in the walls of capillaries and the released fatty acids diffuse into the cell Steps of lipid digestionabsorption Fig 21 able 1 Step 1 Minor digestion of triacylglycerols begins in the mouth by the action of the enzyme lingual lipase followed by gastric lipase that is acidstable and hence is functional even in the acidic environment of the stomach These lipases remove one of the three fatty acids leaving diacylglycerol and free fatty acid as a product triacylglycerol fatty acid diacylglycerol lingual or gastric lipase Step 2 The major digestion of all lipids occurs in the lumen of the small intestines speci cally in the duodenum and jejunem The pancreas releases into the intestine lipases to carry out this process The major enzyme in this process is pancreatic lipase Pancreatic lipase removes the fatty acids from carbons one and three of the glycerol backbone Pancreatic lipase requires for its activity colipase a small protein that binds to both the waterlipid interface and to lipase to anchor and activate the enzyme The pancreatic secretion also includes cholesterol esterase which removes the ester portion of dietary cholesterol ester to facilitate its uptake across the intestinal wall Another minor component of the dietary lipids are phospholipids derived from cell membranes These are processed by the pancreatic enzyme phospholipase A2 The enzyme removes a fatty acid from carbon 2 of the glycerol backbone leaving a fatty acid on carbon 1 and the polar headgroup on carbon 3 lysophospholipid triacylglycerol 2 fatty acids monoacylglycerol pancreatic lipase cholesterol ester cholesterol ester cholesterol esterase phospholipids fatty acid lysophospholipid phospholipase12 Step 3 Because of the poor solubility of lipids they must be solubilized by a biological detergent This solubilizing agent is bile acid that is produced by the liver from cholesterol and converted to bile salts by intestinal bacteria Bile salts act in the absorption of lipids by reversibly forming micelles These micelles are structures with wellde ned sizes and are much smaller than emulsion droplets The arrangements of the bile salts in micelles is such that the hydrophobic waterhating portions are removed from contact with water by interacting with the lipids they are solubilizing while hydrophilic waterloving groups remain exposed to the water Bile salts form mixed micelles with lipids such as 2 monoacylglycerol phospholipids fatty acids cholesterol and fat soluble vitamins These mixed micelles have disklike shapes wherein the phospholipids and fatty acids form a bilayer and the bile salts occupy the edge positions During triacylglycerol digestion by pancreatic lipase free fatty acids and monoacylglycerols are released at the surface of fat emulsion droplets Thus the products of triacylglycerol hydrolysis are continuously transferred from emulsion droplets to the mixed micelles Lipid Transport 2 Lipids Triacylglycerol Lingual Lipase Cholesterol esters E Phospholip1ds STEP 1 E Figure 1 Five GaStI ic Lipase steps of lipid digestion and absorption Step 1 is relatively minor Most hydrolysis of STEPZ Pancreas releases 39quot quot39 u lipase small int stine t acylglycerolsy cholesterol esterase pancreas as wen as phosphohpase A2 STEP 4 phospholipids Lipids absorbed and cholesterol esters occurs in Step 2 from micelles into STEP 3 0 epithelial cells Liver releases bile acids to solubilize lipid products in mixed micelles STEP 5 Chylomicrons form and travel through lymphatics Step 4 Uptake of lipids by the epithelial cells lining the intestines occurs by passive diffusion from the mixed micelles through the membrane Absorption is virtually complete for fatty acids and monoacylglycerols which are slightly watersoluble due to carboxyl and hydroxyl groups This process is less efficient for waterinsoluble lipids such as cholesterol ester only 30 of which is absorbed After absorption of lipid digestion products the micelles remain behind to solubilize other lipid products thus acting as a type of quotshuttlequot Step 5 Cholesterol is converted back to its cholesterol ester form and fatty acids are reattached to glycerol backbones to form new molecules of triacylglycerol These lipid products are then incorporated into a lipoprotein known as a chylomicron see description of lipoproteins below The chylomicrons are then exported into the lymphatic system You may wonder why chylomicrons do not enter the blood This occurs because the fatty acids contained in the triacylglycerol of the chylomicron must be rst delivered to tissues such as adipose tissue and muscle rather than to the liver If the chylomicrons entered the blood they would go straight to the liver where large amounts of fatty acids would be dropped off This would be harmful to the liver since it could become clogged with fat Lipid Transport 3 Table 1 Summary of the steps of lipid digestion and absorption Ste p Location Important Enzymes 1 Minor digestion triacylglycerols mouth and stomach lingual gastric lipase 2 Major digestion all lipids lumen of the small intestines pancreatic lipase cholesterol esterase phospholipase A2 3 Formation of mixed micelles lumen of the small intestines NA 439 Passwe absorptlon thPOIytlc into intestinal epithelial cell NA products 5 Assembly and export of from intestinal cells to the NA chylom1crons lymphatics LIPOPROTEIN S Lipapratein general structure Lipoproteins are characterized according to their densities The lipoprotein densities vary depending on their lipid composition The structure of a lipoprotein speci cally LDL includes a lipid core that varies with each type of lipoprotein see Table 2 surrounded by phospholipids with their hydrocarbon tails facing the interior and their polar head groups eXposed to the surface for interaction with water Fig 2 Stryer 2616 The free hydroxyl group of cholesterol is eXposed on the surface of the lipoprotein to interact with water Likewise proteins see Table 3 sit on the outer surface of the lipoprotein These proteins are referred to as apoproteins Phospholipid Cholesteryl ester Figure 2 Model oflow density lipoprotein Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule Lipid Transport 4 Lipoprotein composition Figure 3 Chylomicrons are the least dense of the lipoproteins because they contain the greatest amount of lipid Figure 3 In keeping with the composition of the diet the vast amount of lipid in the chylomicron is triacylglycerol The 1ipidprotein ratio is 501 Note that the chylomicrons are the only lipoprotein derived exclusively from dietary lipids and are therefore considered the exogenous system Very low density lipoprotein VLDL is made in the liver from triacylglycerol and from cholesterol that is mostly made in the body 90 with a small portion 10 derived from the diet Because these lipids are made in the body this constitutes part of the endogenous system Triacylglycerol still predominates over cholesterol but the proportion is now less than 41 Lipids relative to protein is just 91 in VLDL accounting for the increase in density Low density lipoprotein LDL are actually derived from the very low density VLDL form after the latter has dumped most of its triacylglycerols in tissues such as adipose and muscle Cholesterol is now the predominant lipid being almost 3fold greater than triacylglycerol This is considered the socalled bad cholesterol because it is carried out to the periphery of the body Overall the ratio of lipids to protein is just 31 Like VLDL LDL is part of the endogenous system High density lipoprotein HDL as the name suggests carry the most protein which is present at a 11 ratio with lipids Cholesterol predominates over triacylglycerol at just over 21 This is the socalled good cholesterol because it is carried to the liver for disposal HDL interfaces with both the exogenous and endogenous lipoprotein systems because it donates apoproteins in the formation of both chylomicrons and VLDL P C 100 J39 E E E m 5 P E 5 E 39 P 80 C Figure 3 The major classes of lipoproteins and their relative E 600 P contents of triacylglycerol T 392 E cholesterol C and protein P g 400 C 0 0 T T C 20 T T 0 i Chylo VLDL LDL HDL microns Lipoprotein Type Lipid Transport 5 Transport undpraeessing of lipids in the exogenous system The functions of the lipoproteins are summarized in Table 2 and the functions of the apoproteins are summarized in Table 3 at the end of the notes These table summaries correlate with events shown in gures 4 5 and 6 The exogenous system includes chylomicrons chylomicron remnants and to a small extent HDL Fig 4 Chylomicrons are distributed into the body through the lymphatic system to various nonhepatic tissues primarily adipose tissue and muscle The chylomicrons must deliver fatty acids from the triacylglycerols to these tissues Apoprotein B 48 forms a shell around the lipids to facilitate formation of the chylomicron The surface protein is hydrophilic to aid in solubilization of the chylomicrons From the lymphatics chylomicrons enter the capillaries of target tissues Figure 4 Lipoprotein lipase attached to the inner wall of the capillaries catalyzes the hydrolysis of the triacylglycerols to release fatty acids that enter the tissues Apoprotein CII associated with the chylomicrons activates the lipoprotein lipase molecules After their release from the triacylglycerols the fatty acids traverse the cell membrane to be taken up by the tissue The remainder of the molecule chylomicron remnants contains largely dietary cholesterol and is taken in by the liver by binding of apoprotein E to receptors on the surface of the liver Figure 4 This formation and processing of chylomicrons is termed the exogenous system for lipoprotein metabolism In primarily adipose or muscle chylomicrons interact with lipoprotein lipase LPL activated by apo CII LPL hydrolyzes TAGs fatty acids enter tissues remnants produced with the return of apo CII to HDL Lymph system nascent chylomicrons travel to capillaries Nascent chylomicrons mature by acquiring apo CII C and E E from HDL in the blood chylomicron remnants travel through blood to liver ApoB48 helps with chylomicron assembly chylomicron Liver HDL Elia 22113 remnants D lipoprotein lipase TAG triacylglycerols cholesterol from remnants Q fatty acid from TAG dePOSited in liVer LIVER O chylomicron remnant V liver apo E receptor 39339 cholesterol Figure 4 Exogenous pathway of lipid transport Chylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver HDL in the exogenous system provides in the blood apo C11 and apo E to create a mature chylomicrons molecule Lipid Transport 6 Medical Scenario TC a 59 year old male entered the hospital suffering from chronic gnawing epigastric pain He reported that he had endured mild symptoms of this type since age 18 but had become worse in the last year with bloating atulence and several loose bowel movements daily but without blood pus or mucus In the last few years he had reduced his food intake in an attempt to control pain and diarrhea His weight fell from 62 to 44 kg The past history showed that he had been healthy as a boy while living in the Caribbean on a diet relatively low in fat At 18 he became a merchant sailor and began to experience abdominal pain He described the diet on board ship as higher in fat At 24 he had a perforated duodenal ulcer and fouryears later a partial smallbowel obstruction due to adhesions both of which were treated surgically At the time of the second surgery his blood serum was described as lipemic with a serum triglyceride of 1100 mg100 ml nllt165 but serum cholesterol was only 214 mg 100 ml nl150220 He continued to have recurrent epigastric pain but did not seek medical advice until the present admission Physical examination showed a pale and wasted man His stool contained 226 g of fat per day on a diet containing 100 g of fat Nutrition therapy had been initiated earlier and there was no evidence from blood tests of a residual nutritional de ciency or abnormality of folic acid ascorbic acid carotene vitamins A B12 and E essential fatty acids or amino acids Because of a sudden fall in the patient s hemoglobin he received a transfusion of packed red blood cells The hemoglobin rose to normal and also had a remarkable effect on the plasma triglycerides The levels that had previously been 1750 mg 100 ml fell to just 196 mg 100 ml two days after the transfusion However over the next 2 weeks the triglycerides rose once again to 1750mg 100 ml This patient has a defect of his apo C11 The transfusons temporarily provided him with normal apo CII that in uenced his plasma lipoprotein levels causing the patient s triglyceriderich lipoproteins to decrease After two weeks the normal apo CII was replaced with his defective form and the hypertriglyceridemia returned Transport and processing of lipids in the endogenous system The endogenous system is displayed in Figure 5 The endogenous system involves three lipoproteins 7 VLDL LDL and HDL Very low density lipoprotein VLDL is formed in the liver from triacylglycerol and cholesterol provided by the tissue and with the assistance of apoprotein B100 Figure 5 The VLDL is exported and picks up apoprotein C11 and E in the blood Note that since LDL is derived from VLDL the VLDL molecule contains the apoproteins needed for both VLDL and LDL functions The role of VLDL is to transport and deliver fatty acids to peripheral tissues Triacylglycerols contained in VLDL as in chylomicrons are substrates for lipoprotein lipase in capillaries Therefore VLDL contains apo CII for the same reason and in this way fatty acids synthesized from excess sugar in liver are delivered to other tissues After triacylglycerol hydrolysis by lipoprotein lipase VLDL converts to the low density lipoprotein LDL Figure 5 The density increases because of the loss of the triacylglycerols The role of LDL is to carry cholesterol derived from the liver to other tissues Table 2 LDL travels through the blood to a variety of tissues Apo B100 on the LDL particle binds to protein receptors LDL receptors on the tissues Table 3 and LDL deposits its cholesterol in the cell The processing of LDL will be discussed further below as well as the reason the cholesterol contained in LDL is considered to be bad cholesterol Finally high density lipoprotein HDL contains the smallest percentage of lipids and bene ts the body by being a scavenger of cholesterol from peripheral tissues Table 2 Cholesterol from peripheral tissues leaves the cell Figure 5 HDL contains apo A1 Table 3 that facilitates the formation of cholesterol ester via an acyltyransferase LCAT It is cholesterol ester that is stored in the core of the HDL particle Lipid Transport 7 At primarily adipose or muscle VLDL interact with lipoprotein lipase LPL activated by apo CII LPL hydrolyzes TAGs fatty acids enter tissues LDL are produced w39 h the return of apo C11 and apo E to HDL mature VLDL created by acquiring apo CII B100 B helps assemble C and E E from and export TAG and HDL in mood cholesterol in nascent VLDL LIVER nonhepatic tissues bile acids LDL travels through blood to various tissues 70 liver 30 other Various tissues apo B100 on LDL bind to receptor LDL taken into the cell to deliver 7 cholesterol see Fig 6 for details apo E on HDL binds to liver receptor receptor to deliver cholesterol for processing and excretion as bile acids 9 HDL scavenges cholesterol from nonhepatic fatty and from TAG tissues via CERP facilitating ef ux and apo 39339 cholesterol Al activating LCAT promoting the formation of cholesterol ester TAG triacylglycerols 63 VLDL E lipoprotein lipase Q LDL D apo B100 receptor HDL A liver apo E Figure 5 Endogenous pathway of lipid transport VLDL carries fats to other tissues from the liver LDL takes cholesterol to tissues HDL collects cholesterol from the body back to the liver and also transfers apo E and C11 to form mature VLDL molecules Excess cholesterol in liver is excreted as bile acids for lipid digestion Lipid Transport 8 HDL attaches to liver cell receptors via its apo E protein analogous to the chylomicron remnants Because HDL is a scavenger it is considered to be good cholesterol Consequently higher levels of HDL and a greater ratio of HDLLDL can be protective against the deleterious effects of excess cholesterol Individuals with a lower than normal ratio of HDLLDL should receive appropriate treatment through diet modi cation andor inhibition of cholesterol biosynthesis in the body This is important because of the dangers of atherosclerosis discussed further below Role ofLDL receptor in uptake 0fehalesteral Within the endogenous system LDL is cleared from the blood by uptake into cells Figure 6 This uptake increases the supply of cholesterol in peripheral tissues but at the same time decreases cholesterol synthesis in these tissues The apo B100 protein ofLDL attaches binds to a speci c LDL receptor protein on the surface of the cell Fig 6 step 1 The receptors aggregate to form coated pits containing clathrin step 2 which facilitates LDL internalization into the cell via endocytosis step 3 A sorting endosome forms by combination of the LDL vesicle and an acidic 50 step 4 Acidity causes dissociation of LDL from its receptor which is then recycled to the cell membrane step 5 The LDL and cholesterol ester accumulate in transport vesicles that then fuse with the lysosome in which apo B100 protein is degraded to its component amino acids step 6 Also in the lysosome the cholesterol ester is hydrolyzed to the free cholesterol form step 6 Free cholesterol then moves via NiemannPick C NPC protein to the Golgi apparatus for storage step 7 followed by esteri cation catalyzed by ACAT acyl CoAcholesterol acyltransferase and storage in droplets step 8 ligand and receptor ecycling of dissociate at pH 5 in transport vesicle and LDL d so 39ng endosome lysosome fuse to form rec ptor receptor an step 4 late endosome Clathrin coated pit Step 6 Step 2 NPCl Golgi nedilated free pool of step 8 rans er CE 9 cholesterol ChOICSteml ACAT step 1 B100 9 amino endocytos1s Step 7 step 3 A CE stored in droplets vesicle Figure 6 Steps in the cellular uptake of cholesterol via the LDL receptor NPCl NiemannPick C protein is used to move cholesterol to the Golgi ACAT acyl CoAcholesterol acyltransferase esteri es cholesterol to the ester CE form Lipid Transport 9 Relationship of LDL receptor to hypercholesterolemio and atherosclerosis Cholesterol content in the cell is kept low in part by decreasing the number of LDL receptors When cholesterol levels become excessive the number of LDL receptors may be markedly become decreased to limit eXtraction of LDL from the blood This results in an accumulation of LDL and hence of cholesterol in the blood Buildup of cholesterol in blood vessels can cause blockage which if occurring in arteries leads to atherosclerosis Individuals who have a signi cant genetic defect for the LDL receptor develop atherosclerosis early in development and often die at a young age from heart disease Such disorders fall into the class of familial hypercholesterolemia and are caused by an inability of the defective receptors to take LDL into the cells Table 2 Summary of lipoprotein functions Lipoprotein Function Chylomicron deliver fatty acids as part of triacylglycerol from dietary fat to muscle adipose Chylomicron deliver dietary cholesterol to the liver remnants VLDL deliver fatty acids attached to triacylglycerol derived from liver synthesis to nonhepatic tissues eg muscle adipose LDL from VLDL delivers cholesterol derived from liver synthesis to various tissues HDL collects scavenges cholesterol from nonhepatic tissues and delivers to the liver Table 3 Summary of apoproteins and their characteristics Lipoprotein Apoprotein Function Chylomicron B48 chylomicron formation CII activates lipoprotein lipase E transferred to remnants Chylomicron E binds to liver receptor for chylomicron remnants to enter the cell remnants VLDL BlOO assembly of VLDL CII activates lipoprotein lipase E binds to liver receptor for VLDL to enter the cell LDL BlOO binds to LDL receptor for LDL to enter the cell HDL Al facilitates cholesterol ef uX from cells CII stored on HDL for transfer to chylomicrons and VLDL E binds to liver receptor for HDL to enter the cell Lipid Transport 10
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