Raising HDL Flashcards
Where is HDL made?
70% of HDL is made in the liver and 30% is made in the intestine
What does the enzyme CETP do and what are the consequences?
CETP transfers Cholesterol Esters from HDL to vLDL and chylomicrons in exchange for Triglycerides. This leads to HDL becoming less stable and more prone to degradation.
What is ApoA-I ?
The protein core or HDL.
Why is Triglyceride-rich HDL more likely to be degraded?
It is more susceptible to reduction in particle size due to lipases. Reduction in size promotes the dissociation of ApoAI from HDL, leading to catabolism.
Describe the 3 Steps of the Reverse Cholesterol Pathway.
Step 1: Efflux of cholesterol from peripheral macrophages onto HDL particles via ABCA1, ABCG1 and SRB1 transporters.
Step 2: Uptake of HDL-C into liver via SRB1.
Step 3: secretion of cholesterol from the liver into bile and feces
List 5 Molecular Targets for increasing HDL levels.
ABCA1 transporter, LCAT, Lipases, ApoA1 and CETP.
What is the ABCA1 Transporter and what is its role?
A cholesterol transporter expressed in the liver and on macrophages. In the liver, it plays a role in the secretion of ApoA1 into the circulation and it also promotes the efflux out of macrophages to lipid poor ApoA1.
What does the pharmacological up regulation of ABCA1 lead to?
It leads to increased cholesterol efflux from macrophages and increased ApoA1 secretion from the liver into the blood stream, providing excess acceptors for cholesterol.
Why is ABCA1’s success as a treatment to raise HDL levels limited?
Due to off target effects.
What does LCAT do?
It promotes esterification of free cholesterol to cholesterol esters. (HDL stores the majority of cholesterol in its core as cholesterol esters)
What does LCAT deficiency result in?
Decreased HDL-C and ApoA1. The lack of ability to form mature HDL particles leads to the rapid catabolism of ApoA1.
What is the preclinical evidence for the potential of the small molecule direct activator of LCAT, DS-8190a?
It increased HDL-C levels in monkeys and decreased atherosclerotic lesion area in rodents due to the enhancement of HDL function. The direct binding of DS-8190a to LCAT has also been confirmed.
