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MS 1 Unit VI MCP > Lipoproteins > Flashcards

Lipoproteins Flashcards

1
Q

Basic Principles of Lipoproteins

A
  • blood or plasma lipoproteins are spherical complexes of lipids and specific proteins called apoproteins
  • the lipoprotein complexes include chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDLs) that are transiently formed, low-density lipoproteins (LDLs) and high density lipoproteins (HDLs)
  • lipoprotein particles protect their hydrophobic cargo from their aqueous environment while shuttling them from tissue to tissue
  • when lipid deposition occurs this leads to plaque formation which causes narrowing of blood vessels (atherosclerosis)
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2
Q

Structure of Lipoproteins

A
  • contain an inner hydrophobic core composed of triacyl-glycerol (TAG) and cholesterol esters
  • this hydrophobic lipid core is surrounded by a shell containing amphipathic phopsholipids with their fatty acid chains facing the inner core and polar head groups facing the aqueous exterior; unesterified cholesterol; and apolipoproteins
  • TAG and cholesterol carried by the lipoproteins are obtained by diet (exogenous source) or de novo synthesis (endogenous source)
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3
Q

Size and Density of Blood Lipoproteins

A
  • lipoprotein particles differ in size and density ranging from the largest chylomicron which have the lowest density to the smallest HDLs which have the highest density
  • the density is determined by the proteins to lipid ratio. Chylomicrons contain the highest % of lipid (primarily TAG) and the lowest % proteins
  • can be separated based on electophoretic mobility or based on their density by ultracentifugation
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4
Q

Ultracentifugation of Lipoproteins

A
  • the top is chylomicrons
  • followed by VLDL and chylomicron remnants
  • IDL
  • LDL
  • HDL2
  • ending with HDL3
  • there are families of similar density
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5
Q

Electrophoresis of Lipoproteins

A
  • chylomicron is the origin
  • LDL moves least (B-lipoprotein)
  • VLDL moves slightly more (pre-B-lipoprotein)
  • HDL moves the most (alpha-Lipoprotein)
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6
Q

Composition of Lipoproteins

A
  • has characteristic combination of lipids and proteins which determines density and function
  • chylomicron- 90% triacylglycerol and little protein, phospholipids, and cholesterol
  • VLDL- 60% triacylglycerol, 5% protein, 15% phospholipids, 20% cholesterol
  • LDL- 8% triacylglycerol, 20% protein, 22% phospholipids, 50% cholesterol
  • HDL-5% triacylglycerol, 40% protein, 30% phospholipids, 25% cholesterol
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7
Q

Functions of apoliproteins

A
  • providing recognition sites for cell surface receptors
  • serving as activators for enzymes involved in lipoprotein metabolism
  • some are required as strutural components of the lipoprotein
  • others are transferred between lipoproteins
  • apolipoproteins are divided based on structure and function into classes denoted by letters, and subclasses denoted by roman numerals
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8
Q

Apo A-I

A
  • most abundant apo-LP in HDL
  • synthesized by liver and intestine
  • activates LCAT, which transfers a fatty acid from lecithin to cholesterol to generate cholesterol esters- an activity involved in the maturation of HDL
  • involved in ACT( facilitates both the transfer of cell cholesterol by ABCA1 to nascent HDL and the delivery of cholesterol esters and free cholesterol on HDL to the liver through SR-B1)
  • considered to be an antiatherogenic protein, but genetic defects not always associated with CVD
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9
Q

Apo A-II

A
  • synthesized in liver
  • present with Al in some HDL (more on HDL3)
  • activates LPL and inhibits LCAT- may be proatherogenic
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10
Q

Apo B-100

A
  • produced in liver and binds to lipids provided by MTP (microsomal triglyceride transfer protein) to assemble VLDL
  • one body of apoB-100 for each VLDL particle, and this relationship is retained as the LPs are metabolized to IDL and then LDL
  • measurements of apoB-100 in the plasma reflect particle number, and higher levels of apooB are associated with CVD
  • LDLR binding
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11
Q

ApoB-48

A
  • produced in intestine and is truncated form of apoB100 (48%)
  • involved in chylomicron metabolism- not recognized by the LDLR
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12
Q

Apo CI, CII, and CIII

A
  • ApoCs which can exchanged freely among LP particles are important for TG metabolism because they either interfere with the recognition of apoE by LP receptors or displaces apoE from lipoproteins
  • ApoCII activates lipoprotein lipase
  • ApoCIII inhibits lipoprotein lipase
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13
Q

ApoE

A
  • associated with all LPs except LDL
  • recognized by LDLR and also by the LRP (LDL receptor-related protein: also known as the Remnant Receptor) which mediates the hepatic uptake of chylomicron and VLDL remnants as well as IDL
  • it is apoE that is primarily responsible for clearance of intestinal-derived LPs after a meal and for the clearance of VLDL and IDL before they are converted to LDL
  • ApoE has 3 isoforms (E2, E3,E 4)
  • Apo E3 is most common varient
  • Apo E2 is a risk factor for Type II hyperlipidemia which is characterized by elevation of chylomicron and VLDL remants in the plasma becayse binds poorly to receptors so hypercholesterolemia and premature atherosclerosis
  • Apo E4 associated with Alzheimer’s
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14
Q

Chylomicron Metabolism

A
  • assembled in intestinal mucosal cells
  • carry dietary (exogenous pathway) TAG, cholesterol, fat soluble vitamins and cholesterol esters to the peripheral tissues
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15
Q

Steps of chylomicron metabolism

A

Step 1- Apo B-48 just in chylomicrons, from intestinal mucosal cells, shorter because of posttranscriptional editing. Enzymes involved in synthesis of TAG, cholesterol and phospholipids are found in the SER

  • assembly of the nascent chylomiron requires microsomal triglyceride transfer protein (MTP) which loads Apo B-48 with lipid
  • particles are then transferred from ER to Golgi and packaged in secretory vesicles
  • these fuse with plasma membrane and release nascent chylomicrons to enter lymphatic system and then blood

Step 2-when nascent chylomicron reaches blood it receives Apo-E and Apo-C including apo CII from HDL particles

Step 3-lipoprotein lipase is an extracellular enzyme attached by heparin sulfate to capillary walls in most tissues
-when activated by apo C-II it hydrolyzes TAG yielding fatty acids or glycerol

Step 4- once acted upon by lipoprotein lipase the particle decreases in size and increases in density. APo-C including C-II, are retured to the HDL creating a chylomicron remnant

Step 5- the chylomicron remnant is then taken up by the liver by Apo-E binding to specific Lipoprotein Receptors followed by endocytosis; lysosomal hydrolytic enzymes degrading the remnant components to cholesterol, amino acids and fatty acids and recycling of receptors

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16
Q

Lipoprotein Lipase

A
  • anti-parallel homodimer
  • N terminal domain- lypolytic site
  • C terminal domain binds to the lipoprotein particle and gives substrate specificity
  • upon bind of Apo-C-II the N terminal region supplies the lipid in the lipoprotein to a lid covering a hydrophobic active site in C terminal domain. The lid moves so that the TAG can be degraded
  • Fed (elevated insulin) - adipose tissue LPL expression is increased and muscle LPL is decreased, opposite in fasted
  • patients with a deficiency of LPL or Apo C-II (type I hyperlipoproteinemia) accumulate chylomicron TAG in the plasma and are at higher risk for pancreatitis
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17
Q

Metabolism of VLDL

A
  • produced in liver
  • secreted into blood by the liver as nascent particles containing Apo B-100
  • they obtain Apo E and Apo C-II from HDL particles
  • some TAGs are transferred from VLDL to HDL in exchange for cholesterol ester exchange protein (CTEP)
  • their function is to carry lipids from the liver to the peripheral tissues
  • TAG is degraded by LPL as described for chylomicrons
  • VLDL is converted to LDL in the blood with IDLs or VLDL remnants in transition
  • Apo CII and ApoE are returned to the HDL particles
  • the LDL particle binds to a specific receptor on the surface of hepatiocytes and extra hepatic tissue
  • IDLs can also be taken up by hepatocyes through receptor mediated endocytosis that uses apo E as the ligand
18
Q

Nonalcholic fatty liver

A
  • hepatic steatosis

- occurs in conditions where there is an imbalance between TAG synthesis and secretion of VLDL

19
Q

Function of Cholesterol Ester Transfer Protein

A
  • CETP catalyzes the exchange of TAG from VLDL with cholesterol ester from HDL
  • the greater the concentration of TAG containing lipoprotein particles in the blood the greater is the rate of these exchanges
  • this could explain why high TAG containing lipoprotein particles in blood correlates with greater cholesterol return to liver via VLDL and IDL particles
20
Q

Uptake and Degradation of LDL

A
  • LDL particles contain much less TAG then their VLDL predecessors and more cholesterol and cholesterol esters
  • the function of the LDL particles is to provide cholesterol to the peripheral tissues and return it to the liver
  • they do so by binding the LDL receptors which recognize apo-B 100 and apo E
21
Q

Steps of uptake and Degradation of LDL particles

A

1- LDL receptors are glycosylated transmembrane proteins which are clustered in clathrin coated pits
2- after binding the LDL receptor complex is endocytosed with assistance of clathrin in forming the coated vesicle
-a deficiency of LDL receptor causes elevated plasma LDL-cholesterol (Type II hyperlipidemia)
3- Coated vesicle losses its clathrin coat and fuses with other such vesicles to form endosomes
4- The pH of the endosome drops based on ATP dependent proton pumping into the endosome
-this uncouples the receptor from the LDL particle
-they separate into distinct areas of what is called the Compartment for Uncoupling Receptor and Ligand
5- Receptors are recycled to plasma membrane and endosome fuses with lysosome. Lysosomal hydrolases degrade the LDL (or chylomicron or IDL particles) releasing amino acids, fatty acids, cholesterol and phospholipids

22
Q

Oversupply of cholesterol in the liver

A
  • can decrease expression and increase the degradation of HMG CoA reductase the rate controlling enzyme in cholesterol biosynthesis
  • by similar mechanism described for the regulation of HMG CoA reductase expression, oversupply of cholesterol can also diminish expression of liver LDL receptor (coordinate regulation of the LDL receptor and the rate limiting enzyme in cholesterol biosynthesis
23
Q

Synthesis of Cholesterol Ester by ACAT

A
  • if cholesterol is not needed immediately for a synthetic or structural purpose it can be esterified by Acyl CoA: cholesterol acyl transferase (ACAT)
  • the resulting cholesterol ester can be stored in the cell
  • the activity of ACAT is increased by the presence of an oversupply of intracellular cholesterol
24
Q

LDL Receptor

A

-encoded by a gene created y exon shuffling, short arm of chromosome 19
6 regions:
1)LDL binding region- when acidic residues are protonated calcium cannot bind and the results in a conformation change in domain 2
2) EGF= like and Transducin B subunit like domain forming a propeller shape. This is where the pH depedendent conformational change occurs that causes release of LDL from its receptor
3) N-linked oligosaccharide domain
4) O-linked oligosaccharide domain. Together 3 and 4 extend the LDL binding domain away from the bilayer making it more accessible to the LDL particle
5) 22 amino acids which make a single alpha helical pass through the bilayer
6) Cytosolic domain which associates with the clathrin coated pit and initiates endocytosis when LDL is bound

25
Q

Point Mutations in the LDL Receptor Gene

A
  • genetic mutations leading to familial hypercholesterolemia are mainly deletions, but insertions or duplication occur as well as missence and nonsense point mutations
  • many error in ligand binding- which is bad because that binds LDL
  • lots of errors in EGF precusor- there propellar won’t work there wont be a release of particle from receptor
  • membrane spanning- change in an aa could mean its not going to enter the bilayer
26
Q

Metabolism of HDL

A
  • formed by the addition of lipids to Apo A-1 which is synthesized in the liver and intestine and secreted into the blood
  • HDL serves as a circulating supplier of apoC-II and Apo E
  • nascent HDLs are discoid in shape and contain primarily phospholipids and Apo A, C and E. They take up cholesterol from peripheral tissues and return it to the liver as cholesterol esters
  • when HDL takes up cholesterol it is esterified by lecithin: cholesterol acyl transferase with another product being lysophosphatidyl choline
  • reverse cholesterol transport which involves efflux of cholesterol from peripheral tissue to HDL, esterification by LCAT, binding of the cholesterol ester rich HDL-2 to liver, transfer of the cholesterol esters to the hepatocytes and the release of lipid depleted by HCL3
27
Q

Esterification of cholesterol

A
  • LCAT is activated by Apo-AI and transfers the fatty acid from carbon 2 of PC cholesterol this produces hydrophobic cholesterol ester and lysoPC
  • esterification maintains the cholesterol gradient allowing further uptake of cholesterol from peripheral tissues to HDL
  • as HDL picks up cholesterol ester it converts from the discoidal nascent HDL to the relatively cholesterol poor HDL3 and then to the Cholesterol ester rich HDL3 particle that carriers the cholesterol ester to the liver
  • CETP exchanges cholesterol ester from HDL to VLDL with concurrent exchange TAG from VLDL to HDL
  • this relieves product inhibition of LCAT
  • as VLDLs are catabolized to LDL the cholesterol esters transferred by CETP are taken up by the LDL receptor
28
Q

Reverse cholesterol transport

A
  • the transfer of cholesterol from peripheral cell to HDL, from HDL to liver for bile acid/salt synthesis or disposal via bile and to steroidogenic cells for hormone synthesis is essential for cholesterol homeostatis
  • part of the reason for the inverse relationship between plasma HDL concentration and atherosclerosis and the concept that HDL is the good cholesterol carrier
  • the efflux of cholesterol from peripheral tissue is catalyzed by ABCA1. Tangier disease results from a rare deficiency of ABCA1 whcih leads to absence of HDL particles because of degradation of lipid free apo A-I
  • the uptake of cholesterol esters from the liver involves the SR-B1 that binds HDL on the surface of hepatocytes and selectively takes up cholesterol esters from the particle
  • hepatic lipase which degrades TAG and phospholipids also participates in the conversion of HDL2 and HDL3
29
Q

Oxidized Lipoproteins and Plaque Formation in an Arterial Wall

A
  • macrophage possess high levels of scavenger receptor activity. These scarvenger known as scavenger receptor activity (SR-A) can bind a range of ligands causing endocytosis of modified LDL where the lipid or apoB have undergone oxidative damage
  • the scavenger receptor is not regulated by intracellular cholesterol concentration
  • the macrophage consume excess oxidized LDL and become foam cells
30
Q

Steps of foam cell participation

A

1- in response to endothelial injury (caused at least in part by oxidized LDL) monocytes adhere to endothelail cells, moveto the subendothelium (intima), and are converted to macrophages

2-macrophages consume excess modified (oxidized) lipoprotein becoming foam cells

3- foam cells accumulate, releasing growth factors and cytokines that stimulate the migration of smooth muscle cells from the media to the intima. There the SMCs proliferate, produce collagen, and take up lipid potentially becoming foam cellls

4- low affinity, nonspecific and nonregulated scavenger receptors take up modified LDL

5- High affinity receptors specific for LDL are downregulated when the cell has sufficient cholesterol

31
Q

LDLR

A
  • expressed in most cells and regulates the entry of cholesterol into cells
  • tight control mechanisms alter its expression on the cell surface depending on need
  • recognized ApoB100, ApoE
  • deficiency causes Familial Hypercholesterolemia
32
Q

LDLR-Related Protein

A
  • also known as the apoE receptor or the CMR receptor
  • mediates the uptake the chylmicrons remnants and VLDL
  • mediates the metabolism of the major apoE containing LPs, including, CMR and IDL but is not involved in LDL metabolism
33
Q

PCSK9

A
  • protein that modulates the LDLR
  • up regulation causes degradation of the LDLR and elevation of LDL
  • down regulation does the opposite and is associated with lifelong decrease in LDL and lower risk CAD
34
Q

Scavenger receptor A

A
  • mediates the uptake of oxidized LDL into macrophages (recognize modified form of LDL but not native LDL)
  • in contrast to the exquisitely regulated LDL receptor, high cellular cholesterol does not suppress scavenger receptor, enabling the subintimal macrophages to accumulate abundant cholesterol, become foam cells, and form fatty streaks (early atherosclerosis)
35
Q

Scavenger receptor B

A

-includes CD36 and SR-B1. Uptake of cholesterol from HDL by the liver and steroid producing cell depends in part on the scavenger receptor class

36
Q

Plaques and Cardiovascular Disease

A
  • as the plaque within a blood vessel matures a cap forms over its expanding roof partially occluding the vascular
  • vascular smooth muscle cells migrate from the tunica media to the subintimal space and secrete plaque matrix materials and metaloproteases that thin the fibrous cap
  • the thinning continues until the cap ruptures exposing the cap contents to procoagulants within the circulation
  • this leads to thombus formation
  • if the thrombus comlpetely occludes the blood vessel lumen then an acute myocardial infaraction can occur
37
Q

Standard Fasting Lipid Panel

A

-total cholesterol : enzymatic (cholesterol esterase)
-triglycerides: enzymatic (lipase)
-HDL-C: direct after precipitation of Apo B liporproteins
-VLDL-C: estimated as TG/5*
-LDL-CL calculated by Friedewald formulation*
TC= LDL-C +HCL-C +VLDL-C
*LDL-C = TC- [HDL + VlDL (TG/5)]- not valid if TG >400 mg/dl
-Non-HDL cholesterol (total cholesterol- HDL-C)

38
Q

Dyslipoproteinemia

A
  • dyslipidemia
  • constitute a major risk factor for atherosclerosis and cornary artery disease
  • their proper recognition and managment can reduce cardiovascular and total mortality rates
  • most common dyslipoproteinemias rarely cause symptoms or produce clinical signs that are present on physical exam. Rather they require laboratory tests for detection. The concentration of plasma LPs strongly predicts the development of CVD. The most common test is a lipid panal which includes: Total cholester, Triglycerides; LDL-C; HDL-C; Non-HDL-C; TC/HDL-C ration
39
Q

Lipid Panel Misc

A
  • fasting 12-14 to minimize the influence postprandial hyperlipemia
  • eating is increase TG levels, for total and HDL there is only small effect
  • TC, TG, and HDL are measured directly. VLDL is calculated as TG/5 (VLDL is 20% cholesterol) but not valid if TG >400 mg/dl
  • LDL-C is calculated using the Friedewald formula which assumes that TC is the sum of the cholesterol in the 3 major LP classes (LDL + HDL + VLDL). LDL= TC- HDL - TLDL (TG/5)
  • non HDL-C- includes all of the apoB LP particles considered atherogenic
  • total cholesteral/HDL- lower number lower risk
40
Q

Optimal Lipid Values

A

-Total cholestero 50 in females 40 in males

Non-HDL - <4

MS 1 Unit VI MCP (12 decks)

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