Fates of Cholesterol

Where is cholesterol sythesized and where does it go?

• In vertebrates, most cholesterol is synthesized in liver and then is exported as bile salts (to gallbladder), or as cholesteryl esters (more nonpolar than cholesterol, packaged and sent to other tissues)

• Cholesterol also can become hydroxysteroids (to activate transcription) or steroid hormones

In blood, what does Cholesterol become?

• IN blood, cholesterol moves as part of lipoproteins (lipids and apolipoproteins)

• Monolayer of phospholipids on outside

nonpolar cholesteryl esters on inside
-Hydrophilic proteins on outside for targeting cell receptors

What are the four types of lipoproteins in blood?

LARGEST

1. Chylomicrons

2. VLDL

3. LDL

4. HDL SMALLEST

Chylomicrons

1. largest

2. least dense

3. exogenous pathway

VLDL

-Excess carbohydrates and FAs are converted to TAGs and cholesterol gets converted to cholesteryl esters and incorporated into VLDLs, which originate at liver

- TAGs are delivered to adipose and muscle tissue

LDL

- AFter VLDL deliver TAGs and offload some cholesterol to target tissues, they become LDL

LDLs can deliver even more cholesterol to tissues (and macrophages - part of immune system), eventually, LDL return to liver, bind LDL receptors and are taken up by endocytosis

• ENDOGENOUS PATHWAY (VLDL form in liver, eventually return to liver as LDL)

• When cholesterol level in LDL is high, cholesterol synthesis decreases

HDL

• High density (cuz of protein)

• Originate in liver, protein rich particles that contain very little cholesterol. Their role is to pickup cholesterol from extra hepatic cell tissues besides liver) cells and return to liver to offload it

• reverse cholesterol transport

Atherosclerosis

• If sum of synthesized and consume cholesterol exceeds cellular needs, accumulation of cholesterol cna obstruct blood vessel

• leads to heart failure -patients with high levels of LDL cholesterol get this which is why it is bad

• high levels of HDL has no negative correlation

Plaque formation

- LDL oxidized and stick to epithelial cells of artery macrophages are recruited and take up LDL remnants, lots of cholesterol!

become foam cells, which then have so much intracellular cholesterol that they undergo apoptosis

this leads to formation of cholesterol rich plaques

Why is plaque formation problematic

This is problematic because over time, plaques become larger and may break loose

carried through bloodstream to narrow opening

this can be in artery of heart (heart attack) or brain (stroke)

Familal hypercholesterolemia

• Mutations in LDL receptor that prevents uptake of LDL by liver, very high circulating levels of LDL in blood

• Blood levels are so high that atherosclerosis develops in childhood 0 could use statins to combat

• because inhibits HMG-CoA reductase