Lipid Metabolism & CVD Flashcards
(26 cards)
What are the levels of lipoproteins like in CVD?
Elevated LDL
Reduced HDL.
What are the causes of CVD?
Diet and lifestyle
Genetics
Describe the structure of a lipoprotein.
Spherical particles consisting of:
Hydrophobic centre- made of esterified cholesterol, triglycerides.
Hydrophilic coat- consisting of amphipathic cholesterol, phospholipids, and apoproteins.
State the major classes of lipoproteins and what apoproteins they have.
HDL -apoA1 and A2
LDL- apoB-100
VLDL- apoB-100
Chylomicrons- apoB-48
Why are lipoproteins needed for lipid transportation?
Because lipids are usually insoluble in water.
State the functions of apoB lipoproteins
Deliver triglycerides to:
- Muscle for ATP biogenesis
- Adipocytes for storage.
Chylomicrons- Formed in intestinal cells and transport dietary triglycerides: exogenous pathway.
VLDL- Formed in liver cells and transport triglycerides formed in the organ itself: endogenous pathway.
Summarise the life cycle of an ApoB lipoprotein
- Assembly.
- Intravascular metabolism
- Receptor mediated clearance.
How are triglycerides and cholesteryl ester in Chylomicrons formed?
- From dietary fat:
Monoglyceride and free fatty acid.
Both enter the enterocyte (small intestinal lining cell)
Both join together–> Triglyceride produced. - From dietary fat and bile:
Cholesterol
Enters enterocyte through Neimann-Pick C1 like 1 protein (NPC1L1).
Cholesterol becomes esterified–> Cholesteryl ester
How are Chylomicrons assembled?
- apoB48 joins to structure containing triglyceride.
- MTP causes lipidation: addition of more triglycerides.
- MTP also causes addition of cholesteryl esters to the structure.
- Chylomicrons produced. Exit the enterocyte through exocytosis after the addition of a 2nd apoA1. Goes into lymphatic system.
How are VLDL’s assembled?
Formed from free fatty acids in hepatocytes.
MTP lipidates apoB100 forming nascent VLDL that coalesces with triglyceride droplets.
How are chylomicrons and VLDL’s activated?
By the transfer of apoC2 from HDL particles.
Describe the intravascular metabolism of apoB lipoproteins.
Lipoprotein lipase (LPL)- lipolytic enzyme associated with adipose and muscle tissue.
apoC2 helps binding of chylomicrons and VLDL’s to LPL.
LPL hydrolyses triglycerides to free fatty acids and glycerol- which can enter adipose and muscle cells.
Particles of depleted triglycerides that contain cholesteryl ester–> chylomicron and VLDL remnants.
Describe the clearance of apoB lipoproteins.
- LPL causes chylomicrons and LDL’s to be enriched with cholesterol due to triglyceride metabolism.
- LPL dissociates from Chylomicron/LDL
- apoC2 returns to join HDL’s apoE, a high affinity ligand for clearance binds instead. Particles become remnants.
- Remnants moved to the liver and further metabolised by hepatic lipase.
- All of apo48 remnants and half of apoB100 remnants cleared by receptor mediated endocytosis into hepatocytes.
- apoB100 remnants loose triglycerides through hepatic lipase, so contain high levels of cholesteryl ester.
Intermediate density lipoprotein cause LDL to lack apoE, thus only having remnants of only apoB100.
How are LDL particles cleared?
Clearance is dependent on LDL receptors found in the liver.
- Cellular uptake of LDL via receptor mediated endocytosis.
- Cholesterol removed from cholesteryl ester by hydrolysis.
Release of cholesterol causes inhibition of HMG-CoA reductase, the rate limiting enzyme in de-novo cholesterol synthesis.
Down regulation of LDL receptor expression
Cholesterol stored as cholesterol ester.
Why is LDL known as “bad cholesterol”?
- Uptake of LDL from the blood into the intima of the artery. LDL oxidised to form atherogenic oxidised LDL (OXLDL).
- Migration of monocytes (WBC’s) into the intima, where it becomes macrophages.
- Uptake of LDL by macrophages changes them to cholesterol-laden Foam cells that form a fatty streak.
- Release of inflammatory substances from various cells causes division and proliferation of smooth muscle cells in the intima. Collagen deposition occurs.
- Atheromatous plaque formed, of a lipid core (dead foam cells) and a fibrous cap (smooth muscle)
Why is HDL “good cholesterol”?
HDL plays a key role in removing excess cholesterol in plasma and moving it to the liver where it can be removed. This is known as reverse cholesterol transport.
- HDL binds to receptor in the liver that allows transfer of cholesterol and cholesteryl ester into hepatocytes.
- In plasma cholesterol ester transfer protein (CETF) allows transfer of cholesterol ester from HDL to VLDL to LDL, indirectly returning cholesterol to the liver.
What is primary and secondary dislipidaemia?
Primary- occurs through combo of diet and genetic factors.
Secondary- Occurs as a result of another disease.
What do statins do and how do they work?
1st choice drug to treat LDL. Reduces LDL, total cholesterol levels, triglyceride levels. Increases HDL levels.
Mechanism:
- Statins act as competitive inhibitors of HMG-CoA reductase (rate limiting step in cholesterol synthesis in hepatocytes.)
- Lower cholesterol in heptaocytes, increases LDL receptor expression as counter regulation.
- More LDL taken up and cleared by hepatocytes.
What other benefits do statins offer?
- Lower inflammation
- Lower thrombosis
- Stabilise atheromatous plaques
- Reverse dysfunctional endothelial cells.
Give an example of statin and when it should be administered.
Simvastatin, atorvastatin
Orally at night.
Side effects of statin?
Myositis.
Rarely rhabdomyolosis, increased risk if statin given with fibrate.
Fibrates
Causes significant decrease in triglyceride levels . Moderate decrease and increase of LDL and HDL.
1st line treatment in patients with high triglyceride levels.
Example of fibrate
bezafibrate, gemfibrozil.
Side effects of Fibrate
Myolitis GI symptoms pruritis rash rhabdomyolosis.
