What are the major classes of lipoproteins?
Chylomicrons (stores and transfers dietary fats). VLDL (transfers fats to other tissues). HDL (helps transport cholesterol and form chylomicrons)
What is this particle? What are its different parts?
It is a chylomicron. It has a hydrophobic core (cholesterol, TGs, lipids), a phospholipid/protein shell and apoproteins (B-100).
How do free fatty acids get from your food to you muscle or fat?
Exogenous pathway: the food is processed in the small intestine where the FFAs are packaged into chylomicrons. LPLs (lipoprotein lipases) in the capillaries release the FFAs from the chylomicron and the chilomicron goes back to the liver via the LDL receptor.
How does the liver distribute FFAs to various tissues that need it?
Endogenous pathway: it makes VLDL which goes into the capillaries, is cleaved by LPLs to release FFAs into tissues and it then becomes IDL. IDL can either return to the liver or turn into LDL and transport cholesterol.
What molecules can bind to the LDL receptor?
Those expressing ApoB-100 and ApoE (VLDL remnants, IDL, and chylomicron remnants)
What molecules can bind to ApoE-R and LRP (LDL receptor-related protein)?
Those expressing ApoB-100 and ApoE. These are the back up receptors for the LDL receptor.
What molecules can bind to scavenger receptors?
These receptors are generally not specific or regulated. They are important for HDL uptake.
How does our body synthesize chylomicrons?
Digestive TGs are processed in the SER. The RER makes ApoB-48. Microsomal TG transfer protein assembles nascent chylomicrons (ApoB-48 + TGs). HDL transfers ApoCII (LPL activator) and ApoE (LDL receptor uptake) to the nascent chylomicrons, making it a mature chylomicron.
What would happen to muscle activity in a patient that had a deficiency in HDL?
It would decrease. HDL transfers ApoCII to chylomicrons so that LPL can be activated and cleave TAGs at muscle. Without LPL would never be activated.
How is VLDL synthesized in the liver?
ApoB-100 is made in RER. TGs are transferred from the SER by MTP and the VLDL is processed in the golgi. Finally HDL transfers ApoCII and ApoE to the now mature VLDL.
What happens to VLDLs after they provide fatty acids to muscle and fat?
50% of VLDL remnants return straight to the liver. Another portion is converted into IDL particles that further interact with LPL and release more fatty acids, then return to the liver. A final portion of IDL is converted to LDL. LDL goes on to deliver cholesterol to peripheral tissues and other bad things.
What controls the level of LDL receptor synthesis?
Cholesterol. Decreased levels of cholesterol cause SCAP and SREBP to dissociate from the ER membrane and go to the golgi membrane. Here, proteases release the DNA-binding domain of SREBP and it travels into the nucleus. Here it stimulates HMG-CoA reductase and LDL-R synthesis. When cholesterol builds up it binds to SCAP again and takes SCAP-SREBP back into the ER.
How do we get cholesterol from the peripheral tissues back into the liver?
The enzyme LCAT transfers cholesterol from cells to HDL where they are esterified. HDL can deliver them to the liver or can trade them off to chylomicrons or VLDL (which go to the liver) for TAGs or phospholipids via the CETP enzyme.
How would cholesterol transfer at cells be affected in someone with a failing liver?
The live makes LCAT. LCAT esterifies cholesterol, which drives it from the cell into the HDL core. If someone had liver failure, this process would be impaired.
What determines if cholesterol needs to be taken out of peripheral tissues or not?
LCAT enzyme and ABC1 enzyme (transports cholesterol to cellular membrane)
What is the direct pathway for HDL to get into the liver?
Scavenger receptors (SR-B1)
How do atherosclerotic plaques form?
Endothelial damage -> Cellular ADHESION MOLECULES bind -> Monocytes and T-cells attach to sticky surface and migrate to sub endothelial space -> MACROPHAGES TAKE UP OXIDIZED LDL CHOLESTEROL -> Lipid-rich foam cells form -> Fatty streaks and plaques form
What makes macrophages the culprit for formation of athersclerotic plaques?
They have LDL and scavenger receptors. Scavenger receptors are not regulated by blood cholesterol levels and, especially when they are oxidized, LDL cholesterol is taken into macrophages without regulation…forming the foam cells.
A patient comes to see you with very high levels of LDL in his blood stream. His father and brothers all have a similar condition. What mutations are likely to cause the condition present in this patient?
LDL-receptor and ApoB-100 mutations in Familial Hypercholesterolemia. These make it so LDL cholesterol uptake does not happen because it cannot bind to the liver.
A patient comes to your office and his lab results are back for his military physical. You note that his blood plasma levels of triacylglycerides and cholesterol are quite high. He, being a young lad, is likely to have a genetic mutation in what gene?
Dysbetalipoproteinemia which is a mutation in ApoE. TAGs and cholesterol are remnants of VLDL, IDL and chylomicrons. VLDL, IDL and chylomicrons all rely on ApoE to get back into the liver for metabolism. If they don't, their remnants accumulate.
You miraculously come to the realization that your patient is unable to process chylomicrons and VLDL, resulting in decreased FFA release into muscle and fat. What condition might this patient have?
Hypertriglyeridemia. This results in a defect of LPL or apoC-II because these are necessary for release of FFAs from chylomicrons and VLDL.
A patient comes in and you discover that peripheral tissue levels of cholesterol are very high. The patient also has enlarged, yellow tonsils. What condition might this patient have?
Tangier's disease. It is a mutation in ABC-1 that messes up the unidirectional reverse transport of cholesterol from peripheral cells to HDL.