6. Lipoprotein Chemistry Flashcards
storage fats made of 3 FAs and a single glycerol backbone. Most often mixed
TGs
are independent risk factor of CV disease and if over 1000 increase risk of pancreatitis
Triglycerides
precursor for bile acids and steroids
key for membrane of cells
enriched in lipid rafts in areas key for signal transduciton
Cholesterol
How is cholesterol cytoxic?
excess: forms chol crystals, triggers apoptotic paths, forms toxic oxysterols, fucks with membrane and promotes atherosclerosis
Key four steps of Cholesterol Synthesis
- Acetate –> 6C mevalonate
- Mevalonate–> 5-C isoprene
- 6 isoprenes–> 30-C linear squalen
- Squalene cyclizes to make four ringed cholesterol
What enZ takes HMG CoA–> mevalonate
HMGCoA reductase
What is the RLS and point of regulation for cholesterol synthesis and target of CV drugs?
HMG CoA reductase
Takes AcetylCoA + Acetoacetyl-CoA–> HMG CoA
HMG CoA Synthase
Squalene–> cholesterol is significant because
where plants and animals diverge
we have cyclase to cyclize squalene to cholesterol
Most cholesterol is made in the ______ then exported as:
in liver
exported as bile acids, cholesterol or cholesteryl esters
Whats the role of bile acids
emulsifies fats: have taurocholic acid that surrounds fat drops to increase SA for attack by lipases
Adrenal gland makes______ from cholesterol
Gonads make_______ from cholesterol
mineral and glucocorticoids
progesterone/androgens/estrogens
Which is more non polar: cholesteryl ester or cholesterol
CE!; have FA esterified to oxygen
the FA comes from fatty acyl CoA thus more hydrophobic cholesterol that can’t enter membranes
How are Cholesteryl esters (CE) transported?
via lipoproteins to other tissues or stored in liver
What is carried on lipoprotein particles?
Cholesterol and lipids
Whats is the surface and interior of lipoproteins?
Just surface = apoliproteins made of proteins with a phospholipid monolayer
Inside is loaded with Cholesterol, TGs, CEs
What are ‘cholesterols’ are directly athrogenic?
LDL, LPa, IDL, VLDL remnants
Has apo48 on surface (some others) and is largest lipoportein
Chylomicron
fnx of chylomicron
deliver chol + TG from gut to tissues and liver
What is apo structure of VLDL?
Where is VLDL made?
apoB100 and others
made in liver
Fnx of VLDL
delivers TG to tissues as fatty acids via LPL
short lived liporotein bteween VLDL and LDL
IDL; has apoB100
Has apoB-100 only
LDL; stays in circulation much longer then other lilpoproteins
this is homologous between LDL and plasminogen
Lp(a)
has apoA-1 and ApoA-2 on surface
HDL
Characteristics of apolipoprotein
solubilize lipoprotein in circulation, can change confirmation to adjust to content; can activate or inhibit plasma enZ and have ligands for cell surface receptors
ApoC II and ApoCIII are on
chylomicrons, VLDL, HDL
Key features of Exogenous pathway of cholesterol transport
Eat fat + bile acids–> chylomicrons take up chylomicrons from intestines (have ApoE, CII and B-48)
in capillaries, LPL will release FFA to adipose, tissues and muscle
Remnants from LPL transported by B-48 and ApoE to liver
Key features of Endogenous pathway
Liver releases VLDL (have ApoE, CII, B100) and go to capillaries where LPL will release FFA to adipose/tissue and muscle
IDL is whats left and can to to LDL
OR
Extrahepatic: release HDL (apoA-! or A-II) –> LCAT to just ApoE and B100–> LDL
Events in intestine
- Biles emulsify fats–> make mixed micells
- intenstinal lipases degrade TGs
- FAs and other taken up and converted back to TG
- TG incorporated with chol and apolipoproteins into chylomicrons
- Chylomicrons move through circulation
- LPL activated by ApoC-II In capillary takes TG–> FA and glycerol for use
What activates LPL?
ApoC II
LPL takes TG —–> FA and glycerol
mediates intestinal cholesterol and TG absorption
NPC1L1
What drug targets NPC1L1
Ezetimibe to decrease absorption of TG and cholesterol
What transports plant sterols back into intestinal lumen
ABCG5/8
body can’t digest plant sterols
Mutations in ABCG5/8 is called
Sitosterolemia; autosomal Recessive
pts that absorb lots of plant sterols–> accumulate in blood and tissues causes tendon and subQ xanthomas and increased risk of premature CHD
Sitosterolemia: auto Recessive defect of ABCG5/8
What is the main Apo that transports lipids in chylomicrons?
ApoB 48
Chylomicrons: carry TG and are made from:
Chylomicrons are essential for:
Content of chylomicrons in TG:Chol
dietary TG fatty acids + cholesterol from sm. intestine
dietary fat and fat souble vitamins
10:1 (mostly TG)
In normolipidemic people, chylomicrons are in plasma for how long after a meal:
3-6 hours
should be none 10-12 hours after a fast
ApoE is aquired form
HDL
ApoB 48 is made by:
inestinal epithelial cells and is 48% wt of apo-100
What is the significance of ApoC-II?
activates LPL to allow FFA release for fuel in adipose, heart, skeletal muscle
Where is LPL found and what do we need it for
bound to capillary endothelium in skeletal, heart, adipose
Key for hydrolysing TG from chylomicrons or VLDL into FFA
Process of hydorlysis for LPL
TG–>DAG–>MAG
What is the end result of LPL hydrolysis
get a ‘shrunken’ TG rich particle whre cholesterol phospholipids and apolipoproteins are transfered to HDL
HIgh glucose–> insulin release stimulated–> LPL is transcriptionally_______
upregulated in adipose
In prolongued fasting or diabetic ketoacidosis; LPL activity willl _____
fall; prevents storage of Fatty acids
Where do chylomicron remnants deposit their cholesterol?
Liver; do so after depleated of dietary TG via LPL
Chylomicrons –> liver to dumpo off dietary CHOLESTEROL
When chylomicrons get to liver, which apo is degraded?
apo-48
What Apo is a necessary ligand so chylomicrons can get endocytisized in liver via LDL-receptor or LRP?
chylomicrons have ApoE as ligand to get into liver
What part of chylomicrons are transfered to HDL?
Surface lipds and C proteins
What is left over in a chylomicron once it’s been depleated by LPL in caplillaries and in the liver?
–rest of chylomicron has ApoB, ApoE, some ApoC and depleated of TG adn enriched in CE
in plasma lipid metabolism, this dude key for backup receptor needed for uptake of apoE enriched remnants of chylomicrons adn VLDL
LRP:::: LDL receptor related protein
What dysfnx do we see in type III hyperlipoproteinemia
absence of fnx apoE: so no clearance by LDL receptor and LRP–> get increase TG and cholesterol dense lipoproteins in the plasma.
VLDL transports _____ lipids
endogenous
Where are VLDL made?
in liver when TG production is stimulated d/t increase in FFA or increased synthesis of FFA from liver
What makes of core of VLDL
where does VLDL go form liver
CE’s + TGs (from excess FA or excess carbs) + cholesterol –> to core of VLDL
–> to peripheral tissues
What apos are in VLDL
ApoC I, ApoC-II, ApoC-III and apoE al made in liver
What is the role of Microsomal triglyceride transfer protein?
transfers TG to VLDL core
tranfsfers TG to chylomicrons in intestine
Pt cant make any ApoB containing lipoporteins (chylomicrons, VLDL or LDL), what the heck?
dysfunctional MTP = abetaliporpoteinemia (Vit deficiency, fat in stool, devo delays)
