Cholesterol and Lipoproteins Flashcards
5 functions of lipids
- Energy storage
- Major components of cell membrane
- Signalling molecules
- Required to solubilise fat soluble vitamins
- Biosynthetic precursors
What is cholesterol?
- 25% from diet or synthesised in the liver
- Insoluble in blood plasma transported with a carrier
- Lipoproteins are particles found in plasma that transport lipids
What are lipoproteins?
- The principal means of lipid transport in blood
- Share a general structure, different ratios protein: lipid
- Classified according to density & chemical proteins
4 classifications of lipoproteins
- Chylomicrons
- VLDL
-LDL - HDL
Structure of lipoproteins
Generalised structure
External monolayer contains phospholipids, cholesterol and Apollo proteins
Cholesterol esters and triacylglycerols are located in the particle core
Lipid+ apolipoprotein
Lipoprotein
- mediated by specific protein strands embedded in the surface of lipoproteins
- determine start and end points for cholesterol transport to particular tissues in the body
4 major classes of apolipoproteins
- ApoA
- ApoB
- ApoC
- ApoE
Synthesis of apolipoproteins
- Synthesis in intestine regulated by dietary fat intake
- Synthesis in liver also controlled by hormones & drugs
E.G. - Insulin, glucagon, sex hormones
- Alcohol, statins, fibrates
Apolipoprotein function
Regulate key enzymes in lipoprotein metabolism
- apoC- II for lipoprotein lipase
- apoA- I for lectin- cholesterol acyltransferase
Are ligands for interaction with lipoprotein receptors, targeting lipoproteins to the correct tissues
-apoB100 and apoE for LDL receptors
- Apo-I for HDL receptors
Structure of LDL
Apo B
Surface monolayer of phospholipids and free cholesterol
Hydrophobic core of triglycerides and cholesteryl esters
Structure of HDL
Apo A-I
Apo A-II
Surface monomer of phospholipids and free cholesterol
Hydrophobic core of triglycerides and cholesteryl esters
Lipid transport by lipoproteins
- chylomicrons transport triglycerides and cholesterol in blood
- triglycerides are hydrolysed by lipoprotein lipase to fatty acids, taken up by target tissues and used for energy production
- Chylomicros shrink, remnants back to liver
- VLDL are made by liver & transport lipids to target tissues, acted on by lipoprotein lipase to release fatty acids & taken up by target tissues
- VLDL remnants remain in the blood, become LDL that are then taken up by target cells by the LDL receptor, digested in the lysosome to release the cholesterol
- HDL have the opposite function to LDL and can remove cholesterol from tissues. HDL are synthesised in the blood and acquire their cholesterol by extracting it from cell membranes and transporting back to the liver
- Liver is the only organ that can dispose of significant quantities of cholesterol, in bile salts
Lipoprotein receptors
- Membrane bound receptors to enable cholesterol entry to hepatic and peripheral cells
- LDL receptor, binds apoB-100 or apoE
- LDL receptor gene expression is regulated by intracellular cholesterol concentration
- Binding of LDL to receptor stimulated endocytosis
LDL receptor
LDL is released from the receptor in the endosome, and the receptor is recycled to the plasma membrane
Cholesterol is then released and used as required
e.g. for membrane synthesis, steroid hormone synthesis
Control of LDL receptor activity
- High intracellular levels of cholesterol suppress LDL receptor synthesis
- The decreased synthesis of LDL receptor prevents excessive cholesterol uptake by cells
- As a result, excess dietary cholesterol remains in the blood as LDL
- Potentially deleterious consequences
HDL
Good cholesterol
- high blood levels of HDL correlate with low incidence of atherosclerosis
- HDL is resistant to oxidation
- Scavanges cholesterol from cells and other lipoproteins and returns to the liver, excreted in bile
- HDL can protect against atherosclerosis through reverse cholesterol transport
What is FC & CE?
FC= free cholesterol
CE= cholesterol ester
Dyslipidaemias
-Mutations affecting the LDL are associated with the most common inherited form= familial hypercholesterolaemia (FH)
- Cells lacking functional LDL receptors cannot take up LDL
- the amount of circulating LDL increases, excess cholesterol is deposited in the arteries leading to enhanced risk of developing atherosclerosis
- Other hereditary hypercholesterolemias relate to genetic defects in structure of apolipoproteins
Cholesterol & atherosclerosis
- cholesterol= in cell membranes
- High serum levels indicative of risk of cardiovascular disease
- A major constituent of atherosclerotic plaques is cholesterol enriched LDL
Clinical manifestation of Atherosclerosis
Cardiac
Cerebral (stroke)
Peripheral (pain, ischaemia, ulceration, gangrene)
What two organs control blood cholesterol levels
Liver: produces cholesterol and bile acids
Intestine: absorbs cholesterol from food and bile
What are statins?
Prevent cholesterol synthesis in the liver
E.g. Simvastatin, atorvastatin, rosuvastatin
- Lower plasma cholesterol primarily by inhibiting HMG- CoA reductase
- resultant lowered intracellular cholesterol leads to increased expression of the LDL receptor
- More LDL receptors increase uptake of cholesterol from the blood
What are cholesterol absorption inhibitors?
- prevent uptake from the intestine
E.g. ezetimibe
What are fibrates?
Reduce triglycerides and increase HDL, less effective LDL
E.g. gemfibrozil, fenofibrate
