Cholesterol and HDL metabolism Flashcards
What is HDL
Smallest but most dense lipoprotein
Good cholesterol
carries cholesterol from tissue back to liver
excreted in bile
low levels increase risk for heart disease
What is reverse cholesterol transport
Pathway that uses HDL to carry excess cholesterol from non-hepatic cells back to the liver for excretion into bile
Why is HDL referred to as good
HDL is referred to as “good” cholesterol because it is cholesterol
that is being removed from your body and will not contribute to
atherosclerosis
Main organ of cholesterol synthesis and excretion
liver
How much cholesterol is excreted per day
1g
Step 1 of reverse cholesterol transport
Formation of nascent HDL
Step 2 of reverse cholesterol transport
HDL maturation
Describe formation of nascent HDL
Derived from liver products
Consists of ApoA1, FR and phospholipid
ABCA1 transfers FC/PC from liver cells to apoA1 for nascent HDL formation
apoA1- forms a belt around the lipid
Nascent HDL functions as a cholesterol acceptor
Describe HDL maturation
Maturation of the nascent discoidal HDL to spherical HDL through the actions of LCAT
Describe the LCAT reaction
LCAT reaction occurs at the surface of nascent HDL
LCAT binds to apoA1 to become activated
LCAT releases the FA from PC to generate CE
LCAT increases the CE content of HDL
t/F HDL contains a lot of other proteins and lipids
true
Step 3 of reverse cholesterol transport
Delivery of cholesterol from tissues on HDL to the liver
describe the delivery of cholesterol from tissues on HDL to the liver
Uptake of HDL-cholesterol by the liver occurs by scavenger receptor
Uptake of HDL-cholesterol by the liver
produces lipid-poor HDL which recirculate and can pick up more cholesterol from non-liver tissues
Cholesterol from HDL is preferentially excreted into bile into the small
intestine and eliminated in feces
Scavenger receptors have a greater affinity for mature HDL
How is LCAT activated
apoA1 binds it
How does removing cholesterol from tissues via HDL prevent or reverse atherosclerosis
Increasing cholesterol efflux from macrophages in the artery wall will minimize reduce foam cell formation
Reverse plaque formation (plaque regression)
How do you increase HDL levels
Increase HDL levels by:
increasing ApoA1 levels
Increasing LCAT levels
Niacin
What is niacin
Vitamin B3 supplement
Precursor for NAD and NADP
Decreases lipid levels
if taken at high doses causes liver damage
Increases HDL cholesterol and apoA1
moderately effective
How do you increase cholesterol efflux
Provide more cholesterol acceptors –> more nascent discoidal HDL
How do you increase the number of nascent discoidal HDL
Infuse and HDL mimetic
what is an HDL mimetic
artificial nascent HDL that doesn’t have free cholesterol
What is CER-001? Can it reverse atherosclerosis
drug that stimulates reverse-cholesterol transport
Increased HDL in humans
No plaque regression
3 diseases of HDL metabolism? What is the common effect
apoA1
LCAT deficiency
ABCA1-deficiency
Formation of mature HDL is impaired
What is familial apoAI deficiency? What is severity dependent on? Diagnosis? treatment?
Mutation in APOA1 gene
less than 1 in 1 million
Depend on the mutation:
1. Mutations that reduce apoA1 levels –> low HDL, milder cardiovascular symptoms
2. Complete apoAI deficiency –> impaired reverse-cholesterol transport, very low HDL, high risk of early-onset atherosclerosis
Diagnosis: xanthomas, premature atherosclerosis, low HDL
Treatment: no cure, Statins can lower blood cholesterol
What is Familial LCAT deficiency? Symptoms? Treatment?
Very rare
Single nucleotide mutation resulting in no LCAT activity in plasma
Can’t convert nascent HDL to mature HDL
decreased HDL
Corneal opacity and kidney damage
some develop atherosclerosis
Enzyme replacement therapy: Pure LCAT infusion was safe and well tolerated, however it is not sustained long-term and would need multiple injections
