Lipoprotein Metabolism PDF

 Details of Lecturer O Instructor: Dr. Abir Alamro O Email: [email protected] O Course Number: BCH440 O Credit hours: 3 (3+0) O Office hours: every day from 12:00 am (Office N 198) O Pre-requisite: BCH 340  Course Outline...

 Details of Lecturer O Instructor: Dr. Abir Alamro O Email: [email protected] O Course Number: BCH440 O Credit hours: 3 (3+0) O Office hours: every day from 12:00 am (Office N 198) O Pre-requisite: BCH 340  Course Outline Planned Contact Topics Covered Hours Lipoprotein metabolism 6 Cholesterol metabolism 3 Prostaglandins 3 Digestion and absorption of proteins and amino acids in the GI tract. 3 Catabolism of amino acid nitrogen & Urea Cycle 2 Nitrogen balance 2 Catabolism of carbon skeleton of amino acids 5 Biosynthesis of amino acids 5 Conversion of amino acids to specialized products 3 Chemistry and biosynthesis of porhyrins 4 Catabolism of Haem Integration of metabolism 6  Course Assessment O Exam I 25% of the Final Grade - 1hour duration- O Exam II 25% of the Final Grade -1hour duration o Quizz 10% of the Final Grade – 20 min duration O Exam III (Final Exam) 40% of the Final Grade- 3 hours duration  References O Lippincot's Illustrated Reviews Biochemistry O Lechninger's Principles of Biochemistry 4th edition. D. L. Nelson and M.M. Cox, Worth Publishers. O Harpers illustrated biochemistry 25th edition. Robert K. Murray; Darly K. Granner: Victor W Rodwell Lipoprotein Metabolism BCH 440: Metabolism-II  Introduction O Lipid compounds: Relatively water insoluble O Therefore, they are transported in plasma (aqueous) as Lipoproteins TG C PL  Lipoprotein Structure O The plasma jugg & lipoproteins are spherical macromolecular & complexes of lipids - and specific proteins · or (apolipoproteins o apoproteins).  Lipoprotein Structure & -1 & · Polar & · unesterited cholesterol O Outer coat: Apoproteins Phospholipids Cholesterol (Unesterified) - non-Polae O Inner core: · · cholestery/ esters and TC TG Cholesterol ester (CE)  Lipoprotein Structure O These amphipathic compounds are oriented so that their polar portions are exposed on the surface of the lipoprotein, thus making the particle soluble in aqueous solution.  Lipoprotein Structure O The triacylglycerol # and cholesterol carried by the lipoproteins are obtained either from the diet (exogenous source) or from de novo synthesis (endogenous source).  Lipoprotein Structure lipid & O Lipoprotein particles apolipoprotein F'ssdi Js s se constantly interchange. b -51s) = · j % lipids and % Dis ↓ apolipoproteins with + each other; therefore, 2=5 the actual apolipoprotein and lipid content of each class of particles can be somewhat variable. -  Lipoproteins O There are various types of lipoproteins which O ② differ in lipid and protein composition, size, ③ ④ density, and site of origin O Lipoproteins function both to : keep their component lipids soluble as they transport them in the plasma -- provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. - - - TGL Types and Composition of Lipoproteins 355=58 O Chylomicrons > TG - cholesterol O Very low density -O Lipoprotein (VLDL) = TG a Protein O Low density Lipoprotein (LDL) protein cholesterole > - O High density Lipoprotein & cholestrole (HDL) - S -e + j- 5 · slid  Composition of LDL and HDL O LDL: Mostly free cholesterol Protein O HDL c O > - Mostly cholesterol Phospholipid ester More % protein More % phospholipids Approximate size and density of serum lipoproteins low density O Chylomicrons are the large size high lipid lipoprotein particles low Protein lowest in density and largest in size, and contain the highest percentage of lipid and the lowest percentage of protein. Approximate size and density of serum lipoproteins O VLDLs and LDLs are successively denser, having higher ratios of protein to lipid. O HDL particles are ↳the densest. high density small size high Protein Approximate size and density of serum lipoproteins O Plasma lipoproteins can be separated on the basis of their O electrophoretic > - charge mobility, or on the basis of their ② density by ultracentrifugation.  ENERGY STORAGE TRIGLYCERIDE ENERGY PRODUCTION STEROID SYNTHESIS CHOLESTEROL CELL MEMBRANES BILE ACIDS Lipoprotein Electrophoresis -  - - -  & Plasma Lipoproteins O For triacylglycerol transport (TG-rich): - Chylomicrons: TG of dietary origin VLDL: TG of endogenous (hepatic) synthesis O For cholesterol transport (cholesterol-rich): - LDL: Mainly free cholesterol HDL: Mainly esterified cholesterol thank you  Apoproteins Apolipoprotein s O Five major classes (A-E) divided by structure & function O Each class has subclasses as Apo A1, Apo CII O The apolipoproteins associated with lipoprotein particles have a number of diverse functions, such as Q providing recognition sites for cell-surface receptors, ② serving as activators or coenzymes for enzymes involved in lipoprotein metabolism.  Apolipoproteins O Some of the apolipoproteins are required as essential structural components of the particles and cannot be - removed (in fact, the particles cannot be produced without them), whereas others are transferred freely between lipoproteins. Sj u - - transferred freely essential structural between lipoprotein "Can't be removed " =S. = &= y Esin  Metabolism of chylomicrons - & / O Chylomicrons are assembled in intestinal mucosal cells and O ② ③ carry dietary triacylglycerol, cholesterol, fat-soluble vitamins, ⑪ and cholesteryl esters (plus additional lipids made in these cells) to the peripheral tissues. O TAGs account for close to 90% of the lipids in a chylomicron. * I & site of origin diet" exogenue" b Intestine  O Chylomicton))"og" , b APO B-48 · small TAG * CE C Intestine i - assay Metabolism of chylomicrons , Nascent > Chylomicton Il -83 , fresh" & & > - APGE & ② HDL -Apoc2581 E C = cholesterol; O& CM = chylomicron; TAG = triacylglycerol; - CE xi S = cholesteryl esters. Apo B-48, apo C-II, and apo E are - Nascent Chylomicron Is apolipoproteins found as specific components of plasma& lipoproteins. 25 & - Chylomicro (CM) "S 21 * - TAG > CE C - 75 - , APO & & 2 2-2 fresh , & &, is "S. " "O" 80 I & 15 - - & 90% St , S 90 %- Si6 = ⑧ lip - 9 lipase is Insulin Similest &PM G form lipase " 12 Apo -2 & 2916 153 -di Ci & -- InSW/ as - & S - # - & -. N ↑ - S 2 & & * g -3 laysosom glcerely & & - Phosphat glycerol free FA & glucose enzyme & /] 8-s ↓ -X to liver HDL NES Apoc-2 gicerel SPO -. glucose & /10 s 5 ; - , remnant ( , ETAG e Metabolism of chylomicrons: Synthesis of apolipoproteins ABC -48 O Apolipoprotein B-48 APO-482 : is unique to " is" Vougu ER I chylomicrons. Its b synthesis begins on glycosylated o the rough ER; it is - glycosylated as it golgi si is i moves through the RERS RER and Golgi. Metabolism of chylomicrons: Assembly of chylomicrons O The enzymes involved in triacylglycerol, cholesterol, and phospholipid synthesis are located in the smooth ER. Metabolism of chylomicrons: Assembly of chylomicrons O Assembly of the apolipoproteins and lipid into chylomicrons requires microsomal triacylglycerol transfer protein, which loads apo B-48 with lipid. Metabolism of chylomicrons: Assembly of chylomicrons O This occurs before transition from the ER to the Golgi, where the particles are packaged in secretory vesicles. Metabolism of chylomicrons: Assembly of chylomicrons O Secretory vesicles fuse with the plasma membrane releasing the lipoproteins, which then enter the lymphatic system and, ultimately, the blood  Metabolism of chylomicrons: Regulation of lipoprotein lipase activity O Lipoprotein lipase synthesis and transfer to the luminal surface of the capillary is stimulated by insulin.  Metabolism of chylomicrons: Regulation of lipoprotein lipase activity O As the chylomicron circulates and more than 90% of the triacylglycerol in its core is degraded by lipoprotein lipase, the particle decreases in size and increases in density.  Metabolism of chylomicrons: Regulation of lipoprotein lipase activity O In addition, the C apoproteins (but not apo E) are returned to HDL.  Metabolism of chylomicrons: Regulation of lipoprotein lipase activity O The remaining particle, called a “remnant,” is rapidly removed from the circulation by the liver, whose cell membranes contain lipoprotein receptors that recognize apo E.  Metabolism of chylomicrons: Regulation of lipoprotein lipase activity O Chylomicron remnants bind to these receptors and are taken into the hepatocytes by endocytosis.  251 * S hepatic lipase Metabolism of chylomicrons: - Wis rement chylomicton HDL 2 Regulation of lipoprotein lipase -- & ↓ lipoproline lipase activity patie -. , & Chylomicron I ase & Po & VLDL O The endocytosed vesicle then fuses with a protein lipase Yiver lysosome, and the apolipoproteins, cholesteryl esters, and other components of tissued the remnant are hydrolytically degraded, releasing amino acids, free cholesterol, and fatty acids. The receptor is recycled.  Metabolism of chylomicrons: T Hepatic lipase (HL) free f A. ↓ glycerol O HL is bound to the surface of liver cells, where it also hydrolyzes TG to free fatty acids plus glycerol. O This enzyme, unlike LPL, does not react readily with chylomicrons or VLDL but is concerned with TG hydrolysis in chylomicron remnants and HDL metabolism.  Metabolism of VLDL O VLDLs are produced in the liver. O They are composed predominantly of triacylglycerol (approximately 60%), and their function is to carry this lipid from the liver to the peripheral tissues. O There, the triacylglycerol is degraded by lipoprotein lipase, as discussed for chylomicrons.  & nascent VLDL & only APOB-100 + VEDL &, Metabolism of VLDL APOE , AROCK unique O & & O · O & - & ↑ site & of O 35. & VLDL origion & Jo5 - LDL & and 65 % APOE C- 2 - - 91 CO VLDL - rement site & ofI size origion & b density 9) VLDL Release of VLDL O VLDL are secreted directly into the blood by the liver as nascent VLDL particles containing apo B-100. O They must obtain apo C-II and apo E from circulating HDL. Release of VLDL O As with chylomicrons, apo C-II is required for activation of lipoprotein lipase Modification of circulating VLDL O As VLDL pass through the circulation, triacylglycerol is degraded by lipoprotein lipase, causing the VLDL to decrease in size and become denser. Modification of circulating VLDL O Surface components, including the C and E apoproteins, are returned to HDL, but the particles retain apo B-100. Production of LDL from VLDL in the plasma O With these modifications, the VLDL is converted in the plasma to LDL. Production of LDL from VLDL in the plasma O Intermediate-sized particles, the intermediate- density lipoproteins (IDL) or VLDL remnants, are observed during this transition. Production of LDL from VLDL in the plasma O IDLs can also be O taken up by cells through receptor- mediated endocytosis that uses apo E as the O ligand. Transfer of cholesteryl esters (CE) from HDL to VLDL in exchange for triacylglycerol (TAG) or phospholipids (PL) O Some triacylglycerols are transferred from VLDL to HDL in an exchange reaction that concomitantly transfers some cholesteryl esters from HDL to VLDL. O This exchange is accomplished by cholesteryl ester transfer protein. thank you  Metabolism of LDL O LDL particles contain much= less TG than their VLDL precursors, and have a high concentration of cholesterol and cholesteryl esters. I Metabolism of LDL 94 - receptor recycle % 100 & a c receptor O , LDL receptors are CG G negatively charged - glycoproteins that are · clustered in pits on cell - & - & membranes. The intracellular side of the & pit is coated with the & 4 so protein clathrin. * - Metabolism of LDL & binding O After binding, the LDL- receptor complex is internalized by endocytosis Metabolism of LDL O The vesicle containing the LDL rapidly loses its & clathrin coat and as fuses with other similar vesicles, forming larger vesicles called endosomes. Metabolism of LDL O The pH of the endosome falls (due to the proton- pumping activity of do part endosomal ATPase), which allows separation of the LDL from its receptor. Metabolism of LDL O The receptors then migrate to one side of the endosome, whereas the LDLs stay free within the lumen of the vesicle. Metabolism of LDL O The receptors can be recycled, whereas the lipoprotein remnants in the vesicle are transferred to lysosomes 133050 and degraded by june ma e ↓ lysosomal (hydrolytic) PL enzymes, releasing free cholesterol, AAs, FAs, and PLs. O These compounds can be reutilized by the cell. Effect of endocytosed cholesterol on cellular cholesterol homeostasis Cholestero i O The chylomicron LDL-derived % remnant-, IDL-, and -S & cholesterol affects cellular cholesterol content in several ways.  Effect of endocytosed cholesterol on cellular cholesterol homeostasis8- 45 - - - - -&HMG CoA O First, reductase is inhibited om by high cholesterol, as activ Chloe as tele , a result of which, de H40 novo cholesterol Saf ② ① synthesis decreases. & a & rate limiting step rate limiting step & & Gas - L C Effect of endocytosed cholesterol on cellular cholesterol homeostasis gene O Second, synthesis of ↳ Tceptor peg new LDL receptor protein is reduced by & pressi o n deploy & S decreasing the expression of theGadecrease LDL receptor gene, thus limiting further entry of LDL cholesterol into cells. Effect of endocytosed cholesterol on cellular cholesterol homeostasis O Third, if the cholesterol is not required immediately for some structural or synthetic purpose, it is esterified by acyl CoA:cholesterol acyltransferase (ACAT). JS - In to cholesterol- > Cholesterol ester b stone inside the cells  Synthesis of intracellular cholesteryl ester by ACAT & O ACAT transfers a fatty acid from a fatty acyl CoA derivative to cholesterol, producing a cholesteryl ester that can be stored in the cell. - T O The activity of ACAT is ↑ ACAT activity & enhanced in the presence of increased ↑ Intracellular intracellular cholesterol. Cholestere Uptake of chemically modified LDL by macrophage scavenger receptors O In addition to the & highly specific and vipid protein 180 regulated receptor- or oxidize mediated pathway for LDL uptake described before, macrophages possess high levels of scavenger receptor activity.  used ? when it Uptake of chemically modified LDL by macrophage ↳ SR-A- used by macrophages 2. 50 to take scavenger receptors oxLDL scavenger Class A (Inflammation) & LDL-receptor O These receptors, SM-A LOL receptor & - known as scavenger -D & non-specificreceptor class A (SR- OLD - non-regulatete A), can bind a broad · scavenger receptor clase & affinity range of ligands, and & I am & mediate the oxLDLj4j1s s endocytosis of -5 - , - - +i chemically modified (ApoB1. LDL in which the lipid si j components or apo B have been oxidized.  Uptake of chemically modified LDL by macrophage scavenger receptors O Cholesteryl esters accumulate in macrophages and cause their * transformation into - I “foam” cells, which I & j participate in the formation of & , & & · atherosclerotic / plaque.  Metabolism of HDL & O HDL comprise a heterogeneous family of lipoproteins with a · complex metabolism that is not yet completely understood. & S > O HDL particles are formed in blood by the addition of lipid to & apo A-1, an apolipoprotein made by the liver and intestine unige and secreted into blood. O Apo A-1 accounts for about 70% of the apoproteins in HDL. protein) 3 APA1  CE & W site of origion - b (2565& Metabolism of HDL & liver I small Intestine exchresh , % j5 - 52 & & Plasma choline - enzyme = & is O Albumint , & phosphatidylcholi ne:cholesterol - - & - acyltransferase HDL2591 ① (PCAT) & & =& HDL3 I· - Phosphatidylcholine PC 2 J5 : lived -T ↳ CE SI endocytos es protein 2- &il , 51n Y 3-40 O it is %  Functions of HDLs O HDL is a reservoir of apolipoproteins: HDL particles serve as function a circulating reservoir of apo C-II (the apolipoprotein that is apo c-11 transferred to VLDL and chylomicrons, and is an activator of lipoprotein lipase), and apo E (the apolipoprotein required lipoprotein"s for the receptor-mediated endocytosis of IDLs and lipase - chylomicron remnants). function apo E receptor recognise  Functions of HDLs O HDL uptake of unesterified cholesterol: - to e Nascent HDL are disk-shaped particles containing primarily phospholipid (largely phosphatidylcholine) and apolipoproteins A, C, and E. They are rapidly converted to spherical particles as they accumulate cholesterol.  Functions of HDLs O Esterification of cholesterol: When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme phosphatidylcholine:cholesterol acyltransferase (PCAT). This produces a hydrophobic cholesteryl ester, which is ↳ sequestered in the core of the HDL, and Apo A-1 e lysophosphatidylcholine, which binds to albumin. Yso PC - elimention & Reverse cholesterol transport Si excrection O The selective transfer of cholesterol from peripheral cells to Hills HDL, and from HDL to the liver for bile acid synthesis or > - fre & - disposal via the bile, and to steroidogenic cells for hormone synthesis, is a key component of cholesterol homeostasis. O This is for HDL's designation as the “good” cholesterol Choles + carrier. 320  Reverse cholesterol transport O Reverse cholesterol transport involves : efflux of cholesterol from peripheral cells to HDL, esterification of cholesterol by PCAT, binding of the cholesteryl ester–rich HDL (HDL2) to liver and steroidogenic cells, the selective transfer of the cholesteryl esters into these cells, and the release of lipid-depleted HDL (HDL3). cells 5 HDL3 - & O, 1SjOnZiI liver b & HDLz Si Ce Jesu ⑨ PCAT PCATjos(Egl5 blood Stream 3N HDLz si HDLCEd & HDL3j5 = Lipid HDL2 - - des & & & & & & good ( bad C & distory Toge , s  a O ⑧ & > O & T S -  Lipoproteins and Related Clinical Problems O Atherosclerosis and hypertension O Coronary heart diseases O Lipoproteinemias (hypo- and hyper-) O Fatty liver  Role of lipoprotein (a) in heart In disease bland LDL ↑ & - Apocal O Lipoprotein (a), or Lp(a), is a - 5. particle that, when present in - large quantities in the plasma, is associated with an increased risk of coronary - - , heart disease. O Lp(a) is nearly identical in 9 S structure to an LDL particle. - Its distinguishing feature is the presence of an additional ①A CAT apolipoprotein molecule, apo(a), that is covalently &B CAT linked at a single site to apo & L CAT function -) B-100. & - 3 & - enzyme estefication -= - = -55/Plasma  & * orange & &&I - - - 0 = thanks Esterified cholesterol: Linked to fatty acids Hydrophobic (repels water) Non-polar Primarily used for storage and transport Unesterified cholesterol: Not linked to fatty acids (free) Polar (attracted to water) Essential for cell membrane structure and other biological functions References : Lipid maps. cholesterol and cholesterol esters. https://www.lipidmaps.org/resources/lipidweb/lipidweb_html/lipids/simple/cholest/index.htm Haya alkhamis 443200580  The difference between ACAT , PCAT,LCAT 1. A CAT (Acyl-CoA:Cholesterol Acyltransferase): - Location: Found in the endoplasmic reticulum of cells, particularly in hepatocytes and enterocytes. - Role: Plays a role in cholesterol storage within cells. 2. P CAT (Phosphatidylcholine Acyltransferase): - Location: Found in various cell membranes. - Role: Important for membrane lipid composition and fluidity. - Also referred to as LCAT (Lecithin: Cholesterol Acyltransferase) 3. L CAT (Lecithin:Cholesterol Acyltransferase): - Location: Primarily in the blood plasma. - Role: Critical for the maturation of HDL particles and reverse cholesterol transport. References 1. https://lipidworld.biomedcentral.com/articles/10.1186/s12944-021-01498-6 2. https://elifesciences.org/articles/83534 Haya Al-Khamis 443200580