Deletion of
acyl-CoA:cholesterol O-acyltransferase 2 (ACAT2) in mice results in resistance to diet-induced
hypercholesterolemia and protection against
atherosclerosis. Recently, our group has shown that liver-specific inhibition of ACAT2 via
antisense oligonucleotide (ASO)-mediated targeting likewise limits
atherosclerosis. However, whether this atheroprotective effect was mediated by: 1) prevention of packaging of
cholesterol into
apoB-containing
lipoproteins, 2) augmentation of
nascent HDL cholesterol secretion, or 3) increased hepatobiliary
sterol secretion was not examined. Therefore, the purpose of these studies was to determine whether hepatic ACAT2 is rate-limiting in all three of these important routes of
cholesterol homeostasis. Liver-specific depletion of ACAT2 resulted in reduced packaging of
cholesterol into
apoB-containing
lipoproteins (very low density lipoprotein, intermediate density lipoprotein, and
low density lipoprotein), whereas
high density lipoprotein cholesterol levels remained unchanged. In the liver of ACAT2 ASO-treated mice,
cholesterol ester accumulation was dramatically reduced, yet there was no reciprocal accumulation of unesterified
cholesterol. Paradoxically, ASO-mediated depletion of hepatic ACAT2 promoted fecal neutral
sterol excretion without altering biliary
sterol secretion. Interestingly, during isolated liver perfusion, ACAT2 ASO-treated livers had augmented secretion rates of unesterified
cholesterol and
phospholipid. Furthermore, we demonstrate that liver-derived
cholesterol from ACAT2 ASO-treated mice is preferentially delivered to the proximal small intestine as a precursor to fecal excretion. Collectively, these studies provide the first insight into the hepatic itinerary of
cholesterol when
cholesterol esterification is inhibited only in the liver, and provide evidence for a novel non-biliary route of fecal
sterol loss.