Lipid Metabolism 1. Describe the structure and function and classification of lipoproteins.

Structure = triglycerides and cholesterol esters as the core, outside have phospholipid layer, apoprotein and cholesterol Classification & unction = Chylomicron formed in intestine, absorbed in blood, transported to peri.tissue, lipoprotein lipase brea!do"n, release fatty acid, become remnants that rich in cholesterol #LDL synthesi$ed in liver, transported to peri. tissue, in tissue capillary beds chylomicrons bind to lipoprotein lipase, en$yme activated and lipolyse triglyceride component of the chylomicron and yield fatty acids, release fatty acid, become remnants%&DL before becoming LDL LDL 'high content of cholesterol() overflo" path"ay 'goes to the artery and the peri. tissue( *DL 'high content of protein, transported from per. tissue to liver( +. Discuss the ,-ogenous and endogenous path"ay of lipid metabolism. ,-ogenous = Dietary lipid is absorbed in the intestine as chylomicron, in tissue capillary beds chylomicrons bind to lipoprotein lipase, en$yme activated and lipolyse triglyceride component of the chylomicron and yield fatty acids,, remnants are removed from circulation by liver. apo,. containing lipoproteins have high affinity for the receptor than LDL ,ndogenous = /. Discuss the combination mechanisms employed by the liver to remove chylomiron remnants. 0

1. 2hat is the function of *M3 Co4 reductase in the regulation of intracellular cholesterol0 Synthesis of cholesterol

5. 2hat do you !no" about reverse cholesterol transport0 LC46 esterifies cholesterol and *DL molecules become spherical *DL collects cholesterol from peripheral to liver LC46 esterify cholesterol into spherical cholesterol ester Cholesterol.ester.transport.protein 'C,67( e-change ester and triglycerides Cholesterol ester goes to #LDL and LDL, triglyceride goes to *DL *DL become *DL+ 'unstable form( *DL+ internali$ed by scavenger receptor and recycled by *63L en$yme into smaller pre.8. *DL to restart the cycle. #LDL%LDL enriched "ith cholesterol ester needs to be removed thus goes to the liver, metaboli$ed into bile salt 'biliary cholesterol( and e-creted through faeces 9. Describe the function of LDL.receptor in mediating endocytosis. LDL.enriched cholesterol ester bind to LDL.receptor and undergo clathrin 'protein that helps in vesicle formation(.mediated endocytosis LDL is vesicled Lysosome 'containing cholesterol ester hydrolase( split cholesterol ester into free cholesterol molecules LDL.receptor is decreased to reduce upta!e of LDL Cholesterol synthesis is decreased by the reduction of *M3.Co4 reductase activity &ncreased 4C46 formation of droplet for storage :. *o" does S;,<7 'sterol.regulatory element binding proteins( regulate the cholesterol metabolism in response to cholesterol level in the cell0 2hen cholesterol level is abundant, S;,<= is retained in ,; 2hen cholesterol level dropped, S;,<7 is cleaved and released to act as transcription factor &t binds to gene promoter 'LDL.receptor gene & *M3.Co4 gene( *ence more lipid is internali$ed and more cholesterol synthesis ;esulting in high cell cholesterol level and lo" plasma cholesterol level >. Describe the diagnostic use of lipoprotein value. 6o determine the total cholesterol level by measuring *DL and triglyceride *&3* 7rotective against coronary heart disease 7ancreatis L=2 &ncrease coronary heart disease ris! Desirable level

*DL 6;&3L?C,;&D,

4theroslerosis 1. 2hat is minimally modified LDL 'mmLDL( and ho" does the mmLDL causes the development of arteriosclerosis0 2hat do you !no" about o-idative modification hypothesis0 mmLDL is the product of partial LDL o-idation caused by vascular cells of intima. &t causes the development of arteriosclerosis by accumulating in the e-tracellular subendothelial space of the arteries. mmLDL induces vascular cells to produce monocyte chemotactic protein 1 'attract monocyte 'chemota-is( and prevent migration of monocyte 'inhibit monocyte egression from intima(, 3.CS ,M.CS . 6his further stimulates LDL, and its protein component become @ve charge, increase o-idation of LDL to become o-LDL 'heavily negative.charged(. o-LDL recogni$ed by scavenger receptors on macrophage and internali$ed 'non.regulated upta!e of o-LDL(, causing massive cholesterol upta!e. macrophage containing e-cess o-LDL form foam cells, e-erts direct chemotactic effect on monocyte hence stimulate binding of monocyte to the endothelium. 6his result in the release of lipids and lysosomal en$ymes into the intima =-idative modification hypothesis LDL o-idation as an early event in artherosclerosis, o-LDL as one of the important contributors of artherogenesis. o-idi$ed LDL can have the chemotactic effect on the monocyte, also cytoto-ic on the nomal cell. =-idant limit pero-idation, limit chemical manifestation +. Describe the mechanism of diseases progression A. a. ,arly proliferative phase Monocytes attracted to site, enter lesion and mobility inhibited by o-idi$ed LDL. M.CS transform monocyte into macrophage. Macrophage engulf o-LDL via scavenger receptors on their surface. 6hese receptors number are not regulated, so it continuously engulf o-LDL thus forming foam cells. Collection of foam cells form fatty strea!s, pale yello" bulges in the artery "all 'diagnostic( b. 7rogression phase subendothelial smooth muscle secrete 7D3 , &L.1 and 6B . Smooth muscle cells migrate to"ards lumen, synthesis collagen, resulting in the formation of large collagenous cap covering the lesion. Mature plaCue contain necrotic smooth muscle cells, foam cells, cholesterol crystals and esters, macrophage and t.lymphocyte 'gro" slo"ly( c. Late ulcerative phase macrophage and t.cells located at the edges of the plaCue. Macrophage secretes en$yme metalloproteinases that brea! do"n e-tracellular matri-. 6 @ cell secrete y.interferon "hich inhibits collagen formation. 6hese actions cause the cap to "ea!en and rupture, underlying collagen and lipids are e-posed to the blood. 7latelet in the blood aggregate at the site of cap brea!age, hence thrombus develops.

/. 2hat are the role of monocytes and 6.cells in arteriosclerosis initiation and progression0 Monocyte 2hen endothelial cells undergo inflammatory activation, they increase their e-pression of various leu!ocyte adhesion molecules . #.C4M1 adhere monocytes diapedese bet"een endothelial cells to penetrate the tunica intima 6his directed migration reCuires a chemo.attractant . &nteraction of monocyte chemo.attractant protein.1 'MC7.1( "ith its receptor CC;+ M.CS differentiates trapped monocytes into tissue macrophages . ,-press scavenger receptors that bind internali$ed lipoprotein particles . 3ive rise to the arterial foam cell oam cells secrete pro.inflammatory cyto!ines, reactive o-ygen species and matrimetalloproteinases 'MM7s( to degrade the e-tracellular matriMacrophage congregates in a central core in the typical atherosclerotic plaCue and may die, producing the necrotic core of the lesion 6.cells 6.lymphocytes enter the intima &nside the intima . 6.cell may encounter antigens such as o-LDL and heat.shoc! protein of endogenous or microbial origin . 2hen 6.cell receptors bind to the antigens 6.cell can produce cyto!ines that can influence the behavior of other cells present in the atheroma 2ithin the atheroma the helper 6.cells "ill either secrete pro.inflammatory cyto!ines '6*1 cells( or anti.inflammatory cyto!ines '6*+( 3enerally, 6*1 predominate in the atheroma D*eat.shoc!ed protein. protein e-pressed due to stress 'inflammation( 1. 3ive some e-amples of anti.o-idants in preventing atherosclerosis0 #itamin , . Membrane antio-idant . 4ssociate "ith lipoprotein . ;emove free radical E.tocopherol . <iologically active form of #itamin , . &ncorporated into LDL . *igh resistant to o-idation

5. 2hat are the vascular effects of the antio-idant0 &nhibition of leu!ocyte adhesion . Monocytes and macrophages in atherosclerotic plaCues e-press metalloproteinases that degrade the e-tracellular matri- '"hich "ea!en the plaCue and increase the li!elihood of rupture and thrombosis( . Cells loaded "ith the drug 'E.tocopherol( do not bind monocytes as a result of the reduced e-pression of e.selectin 'reduced binding of monocytes stabili$es the plaCue and reduces its accumulation of necrotic material( ;eduction of cellular o-idative inFury . ,ndothelial cells and macrophages rapidly become necrotic "hen e-posed to o-LDL . Cells loaded "ith the drug 'E.tocopherol( are resistant to cytoto-ic effects of o-LDL hence reducing cell inFury and enhance plaCue stability 9. &n the !noc!out and transgenic mouse models, "hat are the effects to the lesion si$e "hen the follo"ing genes "ere !noc!outA a( 3ranulocytes%Macrophage Colony Stimulating actor 'M.CS ( *elp proliferation of monocyte and macrophage &f !noc!out, macrophage decreased and lesion si$e reduced oam cells decreased b( Monocyte Chemotactic 7rotein 1 'MC7 1( Decrease proliferation ;educe lesion si$e c( 774;G 4ctivate transcription Cause 8.o-idation &f !noc!out, lesion si$e increases d( S;.<+ 6he function is to reduce reverse cholesterol transport hence decreasing LDL level and subseCuently help reduce lesion si$e &f !noc!out, lesion si$e increase