Lipoproteins and Cholesterol (Mine) Flashcards
What structural components of cholesterol should we know?
Allicyclic compound (4 fused rings)
one hydroxyl group at C3
sterane ring and hydrocarbon chain
How is cholesterole degraded by cells?
it is not degraded by cells
it must be biochemically degraded or excreted by liver
An excess leads to atherosclerosis
Where is most cholesterol synthesized?
the liver
biosynthesis is inversely proportional to dietary intake
(it is very energy dependent, 18 ATP for one cholesterol)
What are the main steps of cholesterol synthesis we should know?
1 Acetyl CoA adds another and then another via HMG CoA synthase making HMG CoA
HMG CoA becomes Mevalonate using HMG CoA reductase (RATE LIMITING STEP)
What stimulates HMG CoA?
Insulin
Thyroxin
What inhibits HMG CoA?
Statins
glucagon
sterols
high AMP
vit. E
IPP (which is what is made by Mevalonate after the rate limiting step) becomes what important things for cellular function and integrity?
Ubiquinone (ATP synthesis)
Lipid anchors (binds proteins to cell membrane)
When on Statins, cholesterol is not made and neither are these components. Can be myotoxic (good to supplement CoQ10)
What is the step right before cholesterol is finally synthesized and why is it important?
Lanosterol-first time the structure is cyclic
inhibited by antifungals and breast cancer drug, Tamoxifen
(azoles, miconizole, ketoconizole, etc)
What is important structurally about HMG-CoA reductase?
it is an 8 transmembrane protein in the ER with the catalytic domain in the cytosol (means that statins have to get into the cytosol or trigger some kind of 2nd messenger system?)
How do statins work?
they are strong competitive inhibitors of HMG CoA reductase with super high affinity (like 1000x more than HGM CoA)
What is a happy accident caused by statins?
hypocholesterolemic action from increased sterol regulatory element binding protien (SREBP) leads to transcription of LDL receptors and enhanced clearance of cholesterol via LDL receptor-mediated endocytosis
What is a negative side effect of statins?
myotoxic side effects due to statin mediated myopathy caused by depletion of muscle levels of ubiquinone (coq10)
What are some of the fates of cholesterol?
esterified to esters by Acyl CoA:cholesterol acyltransferase
packaged into VLDL and released into blood
How is cholesterol synthesis directly inhibited?
free fatty acids
bile acids
oxysterols
statins
all acting on HMG CoA reductase
How does covalent modification regulate cholesterol synthesis?
HMG CoA reductase is inactive when phosphorylated
active when dephosphorylated
- low energy, high AMP, AMPK,, glucagon inhibit enzyme
- insulin activates enzyme
How does transcriptional control regulate cholesterol synthesis?
binding of TF to promotor on the HMG CoA reductase gene increases its mRNA levels
how does translational and post-translational control regulate cholesterol synthesis?
TC: at protein synthesis level, reduced by vit. E family and oxylanosterols
PTC: protein turnover/degradation level. Enhanced by sterols, oxysterols, and y-tocotrienol
Describe the mechanism of transcriptional control
HMG CoA reductase gene as a sterol regulatory element (SRE) in promotpr region
TF called SREBP bind to SRE
SREBP (inactive) interacts with a protien SREPB cleavage activating protein (SCAP)
in times of cholesterol presence, SREBP-SCAP complex stays in ER due to INSIG binding
in low cholesterol, SREBP-SCAP moves from ER to golgi where SREBP undergoes proteolysis to release mature form of SREBP and translocates to nucleus
mature SREBP binds SRE and promotes transcription of HMG CoA reductase to help increase cholesterol synthesis
What are lipoproteins?
transporters of cholesterol, esters, TAGs, fat soluble vitamins
cholesterol within a lipoprotein is way more soluble than when it is unbound
What is the order of biggest and least dense to smallest and most dense?
chylomicrons
VLDL
IDL
LDL
HDL
Which lipoprotein has the most TAGs and which has the most proteins?
TAGs-chylomicrons (intestine)
proteins-HDL (liver)
What three components are found outside the chylomicron and what are their functions?
ApoB-48-facilitates transport
ApoC-II-activates capilary lipoportein lipase
ApoE-facilitates uptake into liver
What are the three components outside the VLDL and how does it evolve as it becomes LDL?
VLDL-ApoB-100, ApoC-II, ApoE
IDL-ApoB-100, ApoE
LDL-ApoB-100 (helps with uptake into the cells)
LDL becomes “bad” when it cannot get into cells
What are the three components outside the HDL and what are their functions?
ApoA-I: activates enzyme to esterify cholesterol
ApoC-II-activates capillary lipoprotein lipase
ApoE-promotes uptake into hepatocytes
(highest protein and phospholipid content)
Describe chylomicron processing
- nascent chylomicrons are made with dietary lipids in SI and transported thru lymph into blood
- apoprotiens are added to make it a mature chylomicron (ApoC-II and ApoE are added by HDL)
- capillary lipoprotein lipase hydrolyzes triacylgycerols into glycerol and free fatty acids and ApoC-II is released back to HDL
- remnants are endocytosed by liver via binding of ApoE to receptor on liver
how are VLDL, IDL, and LDL processed?
- VLDL are assembled in the liver and released into bloodstream
- capillary lipoproteinlipase hydrolyses TAGs into glycerol and FFA. ApoC-OO is released back to HDL and IDL remains
- cholesterol in IDL is given to liver via binding of ApoE to liver. IDL loses more TAGs via hepatic lpp lipase and ApoE to become LDL
- LDL gives cholesterol to liver and other tissues via binding of ApoB-100 on target cells
Half of IDL is converted to LDL by losing Tags degraded by tissue lipoprotein lipases
What is the major carrier of cholesterol in the blood?
LDL
1500 cholesterol esters per particle of LDL
binds via ApoB-100 receptors
it’s role is to transport cholesterol to peripheral tissues and regulate de novo syntheiss of cholesterol at these sites
LDL receptor releases LDL into what structure?
Endosomes
mutations in these endosomes/receptors can cause familial hypercholesterolemia and the receptors are unable to release the LDL cargo
Describe HDL processing
- disc shaped nascent lipid poor HDL is synthesized in the liver and small intestines
- nascent HDL picks up cholesterol from peripheral tissues
- LCAT esterifies cholesterol and they enter the HDL core making it spherical
- HDL donates and receives ApoC-II and ApoE from chylomicrons. HDL then transfers cholesterol esters to VLDL, IDL, and LDL in exchange for TAGs and phospholipids, facilitated by CETP and delivers cholesterol to liver
What are the benefits of HDL?
reduced risk of CAD
helps to mature chylomicrons
pulls cholesterol out of other tissues (reverse cholesterol transport) (uses ABCA1)
removes LDL cholesterol from periphery and takes it to liver for processing
antioxidant, anti-inflammaotry, antithrombotic, and NO inducing properties
can increase levels with weight loss and exercise as well as certain drugs/omega 3 FAs
What is Type I Hyperlipoproteinemia?
Def. in ApoC-II or defective lipoprotein lipase
increases chylomicrons and TAGs
unable to hydrolyze TAGs in chylomicrons and VLDL
LPL def. is seen in infancy while ApoC-II is seen post adolescence
plasma TAG levels are over 1000 mg/dl
creamy appearance of blood sample
s/s: abdominal pain, acute pancreatitis, xanthomas
tx: low fat diet
What is type II hypercholesterolemia?
LDL receptor is completely or partially defective, unable to recognize ApoB 100 on LDL
increase in cholesterol, TAGs (depending), LDL and VLDL
LDL accumulates under endothelial cells in blood vessels and causes atherosclerosis
Heterzygous-300-500, treat with diet, statins, BABR
Homozygous-over 800, treat with LDL apheresis and liver transplant
s/s-xanthomas, CAD, angina, corneal deposits
How does plasma cholesterol relate to atherosclerosis?
LDL C accumualtes under lining of blood vessels and is oxidized by ROS to oxLDL and continues to accumulate in vessel wall leading to endotehlial injury
this increases vascular permeability and leukocyte adhesions initiating inflammatory responses and influx of macorphages (which turn to foam cells)
foam cells are trapped and become plaques
death of foam cells, platelet adhesions and rec. of Sm.M cells lead to further development of arterial plaques causing atherosclerosis
can lead to MIs
