We have observed that gene deletion and gene knockdown of ACAT2 protects against atherosclerosiswhen VLDL and LDL in plasma are depleted of ACAT2-derived cholesteryl esters. The goal of theresearch in project 1 is to define the mechanisms by which ACAT2 affects cholesterol metabolism andatherosclerosis.
AIM1. We propose to identify how cholesteryl oleate enrichment of LDL promotesatherogeneisis. We will monitor cholesterol metabolism in the intestine and in the liver. ACAT2 is knownto catalyze synthesis of cholesteryl esters for transport into the body in chylomicrons during intestinalcholesterol absorption.
AIM2. ACAT2 is an important component helping to regulate the efficiency ofintestinal cholesterol absorption and we have designed studies to define the specific contributions ofACAT2 together with ABCG5/G8, a transporter that is known to move cholesterol back out of cells afterentry.
AIM2. We hope to determine the relative roles of ACAT2 and ABCG5/G8 in facilitating cholesterolabsorption while limiting plant sterol absorption. The fate of newly absorbed chylomicron cholesterol, mostof which is esterified, is to be efficiently delivered to the liver where the influx of newly absorbed dietarycholesterol provides substrate for many pathways of cholesterol homeostasis. These include secretioninto bile, incorporation into the plasma membrane, esterification by ACAT2 resulting in CE that getsecreted in VLDL or stored in cytoplasmic lipid droplets within hepatocytes.
AIMS. We hope to determinehow ACAT2 in the liver directs the outcome of cholesterol handling. During cholesterol feeding, theamount of hepatic CE storage and secretion rises significantly depending on the type of fat in the diet.Paradoxically, when the ACAT2 gene has been deleted, triglyceride secretion in VLDL is increased whiletriglyceride concentration in the liver is greatly reduced and the levels of cholesterol and cholesteryl esterstored and secreted by the liver remain low, even when dietary cholesterol is fed, effectively preventinghepatic steatosis. The mechanism for this shift in lipid metabolism will be investigated. The data suggestthat ACAT2 activity is integral to the metabolic regulation of cholesterol and triglyceride both of which arestored and secreted by the liver.
AIM4. Studies on the protein structure and active site of the ACAT2protein are also proposed. We have identified a putative 'catalytic triad' reaction mechanism for theenzyme and we have identified specific amino acid residues that appear to form the active site. Inaddition, we have identified the single amino acid residue that appears to interact with the most highlyACAT2-specific inhibitor yet identified, pyripyropene A.
AIMS. We have proposed studies to identifywhether cholesteryl oleate in human plasma can be a biomarker for ACAT2 activity in patients with CHD.Ultimately we would hope that inhibition of ACAT2 in human beings would become a reality providingprevention of CHD and hepatic steatosis.
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