MCP Lecture 2 Flashcards by Abbey Phelps

What is the function of lipoprotein particles and list the different lipoprotein complexes

protect hydrophobic cargo from aqueous environment

chylomicrons, VLDL, IDL, LDL, HDL

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Atherosclerosis

lipid deposition leading to plaque formation

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What is the density of lipoprotein particles determined by?

protein to lipid ratio

chylomicrons have highest % of lipid and lowest % protein = least dense

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What are the functions of apoliproteins?

provide a recognition site for cell surface receptors
activators for enzymes involved in lipoprotein metabolism
structural components

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Apo A-1: function and where is it synthesized?

function: structural protein for HDL, LCAT activator, involved in RCT (reverse cholesterol transport), ligand for ABCA1 and SR-B1 (transfer of cell cholesterol by ABCA1 to nascent HDL and delivery of free cholesterol on HDL to the liver through SR-B1)
synthesized: liver, intestine

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Apo A-II: function and where is it synthesized?

function: structural protein in HDL
synthesis: liver

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Apo B-100: function and where is it synthesized?

function: structural protein in VLDL and LDL, involved in VLDL assembly, LDLR binding
synthesis: liver

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ApoB-48: function and where is it synthesized?

function: truncated form of apoB100 involved in chylomicron formation and secretion unique to chylomicrons
synthesis: intestine

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ApoC-I: function and where is it synthesized?

function: LCAT activator
synthesis: liver

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ApoC-II: function and where is it synthesized?

function: LPL activator
synthesis: liver

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ApoC-III: function and where is it synthesized?

function: LPL inhibitor
synthesis: liver

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Apo E: function and where is it synthesized?

function: recognition by LDL and CM remnant (LPR) receptors (mediates the hypatic uptake of CM and VLDL remnants - responsible for clearance of VLDL and IDL before they are converted to LDL)

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Dysbetalipoproteinemia

Type III hyperlipidemia: elevation of CM and VLDL remnants in the plasma associated with ApoE2

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Alzheimer’s disease

associated with ApoE4

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What are chylomicrons

assembled in intestinal mucosal cells and carry dietary TAG, cholesterol, fat, soluble vitamins, and cholesterol esters to the peripheral tissues

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Describe chylomicron metabolism

step 1: ApoB-48 (N-terminal 48% of the protein used for ApoB-100) - MTP loads ApoB-48 with lipid in ER - transfer from ER to golgi and packaged into vesicles
step 2: nascent chylomicron receives Apo-E (to be recognized by hepatic receptors) and Apo-C
step 3: LPL is activated by apoC-II hydrolyzing TAG to yield FA (stored in adipose, used in muscle) or glycerol (used by liver for lipid synthesis/gluconeogenesis)
step 4: after LPL, particle decreases in size and increases in density - ApoC are returned to HDL (creates chylomicron remnant)
step 5: chylomicron remnant is taken up by the liver by apo-E binding to specific lipoprotein receptor - endocytosis, lysosomal hydrolyic enzymes degrade remnant components to cholesterol, AA, FA - recycle receptors

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Describe the structure of lipoprotein lipase

anti-parallel homodimer each with an N-terminal domain with the lypolytic site and C-terminal domain that binds to the lipoprotein particle (gives specificity)
ApoC-II binds N terminal domain

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What is type I hyperlipoproteinemia?

deficiency of LPL or ApoC-II - accumulate chylomicron TAG in the plasma and are at higher risk for pancreatitis

Describe the metabolism of VLDL

produced by liver, contain ApoB-100
obtain apo E and apo C-II from HDL particles - some TAGs transferred from VLDL to HDL in exchange for cholesterol esters in a reaction catalyzed by CETP
TAG degraded by LPL
VLDL converted to LDL in the blood with IDLs or VLDL remnants observed during transition - apo E and apo C-II returned to the HDL particles
LDL particle binds to a specific receptor on the surface of hepatocytes

What causes hepatic steatosis?

when there is an imbalance between TAG synthesis and secretion of VLDL

What are the three common isoforms of apo E? Which is most common? What is associated with each?

E3 - most common
E2 - least common - homozygous = type III hyperlipoproteinemia with hypercholesterolemia and premature atherosclerosis (bc deficient in clearance of chylomicrons or IDL)
E4 - increase susceptability for Alzheimer’s

What is the function of CETF?

catalyzes the exchange of TAG from CLDL with cholesterol ester from HDL
greater the concentration of TAG, greater the rate of exchanges

What is the function of ACAT?

Acyl CoA: cholesterol acyl transferase
when cholesterol is not needed immediately for a synthetic or structural purpose it can be esterified so that it can be stored in the cell

Describe the steps in uptake and degradation of LDL particles

LDL receptors are glycoslated transmembrane proteins clustered in clathrin coated pits
complex is endocytosed
coated vesicle loses its clatherin coat and fuses with other vesicles to form endosomes
pH of endosome drops - uncouples the receptor from LDL particle, separate into distinct areas called CURL
receptors are recycled and endosome fuses with a lysosome - lysosomal hydrolases degrade the LDL releasing AA, FA, cholesterol and phospholipids

Type II hyperlipidemia

``` familiar hypercholerolemia (FH) autosomal dominant caused by increased activity of a protease that degrades the LDL receptor or by defects in Apo B-100 causes elevated plasma LDL-cholesterol ```

What are the effects of an oversupply of cholesterol?

in the liver: decrease the expression and increase the degradation of HMG CoA reductase (rate controlling step in cholesterol biosynthesis) oversupply can also diminish expression of liver LDL receptor

Describe the structure of the LDL receptor

``` 6 regions 1. LDL binding region 2. epidermal growth factor-like domain - where the pH dependent conformational change occurs that causes release of LDL from receptor 3. N-linked oligosaccharide domain 4. O-linked oligosaccharide domain (3&4 extend teh LDL binding domain away from bilayer- make it more accessible to the LDL particle 5. alpha helical pass through bilayer 6. cytosolic domain ```

What is unique about the gene that encodes the LDL receptor?

created by exon shuffling - contains 18 exons on the short arm of chromosome 19

What is the most common genetic mutation leading to familial hypercholesterolemia?

deletions

What is the function of HDL?

formed in blood by addition of lipids to apo A-1 serves as the circulating supplier of apo C-II and apo E take up cholesterol from peripheral tissues and return it to the liver as cholesterol esters

Describe the esterification of cholesterol

LCAT is activated by Apo A-I and transfers the FA from carbon 2 of PC cholesterol producing a hydrophobic cholesterol ester and lysoPC

Why is cholesterol esterified?

to maintain the cholesterol gradient allowing further uptake of cholesterol from peripheral tissues to HDL

What is CETP?

exchanges CE (cholesterol ester) from HDL to VLDL with concurrent exchange TAG from VLDL to HDL which relieves product inhibition of LCAT

What is reverse cholesterol transport?

transfer from peripheral cells to HDL and then to liver for bile acid/salt synthesis or disposal via bile and to steroidogenic cells for hormone synthesis in order to maintain cholesterol homeostasis

What is the function of ABCA1?

catalyze the efflux of cholesterol from peripheral tissues - transporter and major regulator of cellular cholesterol

What is SR-B1?

binds HDL on the surface of hepatocytes - uptake of cholesterol esters

What causes plaque formation in an arterial wall?

macrophages have a high level of scavenger receptor activity (SR-A) - bind a range of ligands causes endocytosis of modified LDL - consume excess oxidized LDL and become foam cell - foam cells participate in plaque formation

How does thrombus formation occur?

plaque within blood vessel has a cap form vascular smooth muscle cells and secrete plaque matrix material thinning of the plaque continues until the cap ruptures exposing the contents leads to a thrombus formation

What does the LDLR receptor recognize? What is its function?

recognize: ApoB100 and ApoE function: uptake of LDL - regulates the entry of cholesterol into cells *deficiency causes familial hypercholesterolemia

What does the LDLR-Related protein (LRP or chylomicron remnant receptor) recognize? What is its function?

recognizes: ApoE but NOT ApoB100 function: metabolism of apoE containing lipoproteins (CM and VLDL remnants)

What does scavenger class A receptor recognize? What is its function?

recognizes: oxidized LDL function: macrophage uptake of modified LDL; involved in atherosclerosis

What does scavenger class B recognize? What is its function?

recognizes: HDL function: accepts cholesterol from HDL (liver, steroid producting cells)

What is PCSK9?

protein that modulates the LDLR - upregulation causes degradation of the LDLR and elevation of LDL