Lecture 13 BCH 3120 - Familial hypercholesterolemia and atherosclerosis

Familial hypercholesterolemia

An autosomal co-dominant disorder characterized by elevated plasma LDL concentrations and premature atherosclerosis

Atherosclerosis

the buildup of fats, cholesterol and other substances in and on the artery walls

Why is LDL considered the bad cholesterol?

When LDL is too high, it causes thickening of the arteries, which can lead to atherosclerosis.

Why is high blood pressure the first step in cardiovascular disease?

High BP can cause tears in blood vessel endothelium

Microtears in blood vessels allow for what?

the infiltration of LDL into the blood vessels. This triggers the invasion of macrophages because LDLs are in the wrong place.

Eventually what happens to LDLs in blood vessels?

LDLs oxidize and cannot be picked up by macrophages so the macrophage-LDL complex makes foam cells which build up in the artery

Then, after the buildup of foam cells...?

Necrosis begins and foam cells will send messages to smooth muscle cells to promote vascularization (more blood vessels) the wall becomes thicker.

Xanthelasma palpebrarum (eye lids) and cutaneous xanthoma

Deposit of cholesterol-rich materials under the skin

Cause of familial hypercholesterolemia

Most prevalent cause are loss-of-function mutations within the LDLR gene

Allele frequency of LDLR mutation is ...?

High

- 1/500 in general population

- Higher in certain groups

Mutations within LDL Receptor that cause familial hypercholesterolemia

LDLR-null

ER/Golgi trafficking

Ligand-binding

Internalization

LDLR recycling

LDR-null mutation

mutations within exon 1 of the LDLR gene resulting the lack of protein synthesis

ER/Golgi trafficking mutation

mutations causing retention of LDLR within the ER and not transported to the plasma membrane (problems with the packaging and transport of membranes)

Ligand-binding mutation

mutations within the ligand-binding domain resulting in impaired binding to LDL (apoB100)

Internalization mutation

mutations in the intracellular domain of LDLR resulting in inability to internalize LDLR/LDL complex

LDLR Recycling mutation

mutations preventing dissociation of LDLR/LDL complex within the "sorting" endosome and not allowing LDLR recycle back to the plasma membrane

3 ways to control cholesterol homeostasis

1. Dietary intake of cholesterol

2. Rate of endogenous synthesis in the liver

3. Rate of cholesterol use by the cells

Dietary intake of cholesterol treatment

Lower cholesterol intake: reduce animal product intake - avoid eggs, cheese, meat, fat

What enzyme do statins inhibit?

HMG-CoA reductase

Rate of endogenous synthesis in the liver treatment

- Inhibition of HMG-CoA reductase by the competitive inhibitors

- Statins

Rate of cholesterol use by the cells treatment

- Increase cholesterol uptake by the liver

- Statins

- Inhibitors of PCSK9

Statin

competitive inhibitor of HMG-CoA reductase

Effect of HMG-CoA reductase inhibition by statins

- Reduction of de novo cholesterol biosynthesis

- Low cellular cholesterol leads to an increase in SREBP2

- Increase in LDL receptors production

- Clearance of extracellular cholesterol from the blood

- Lowering of cholesterol levels in the blood

Why are statins unable to completely remove LDL from the blood? / Why is the first dose of statins the best?

As statins lower cholesterol, PCSK9 is expressed more so every subsequent dose fights the effects of PCSK9. (PCSK9 degrades LDL receptors)

Solution to why statins can completely remove LDL from the blood?

PCSK9 inhibitor