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J. Biol. Chem., Vol. 283, Issue 16, 10522-10534, April 18, 2008

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Targeted Depletion of Hepatic ACAT2-driven Cholesterol Esterification Reveals a Non-biliary Route for Fecal Neutral Sterol Loss^*

J. Mark Brown, Thomas A. Bell, III, Heather M. Alger^¶, Janet K. Sawyer, Thomas L. Smith^||, Kathryn Kelley, Ramesh Shah, Martha D. Wilson, Matthew A. Davis, Richard G. Lee^**, Mark J. Graham^**, Rosanne M. Crooke^**, and Lawrence L. Rudel^¶1

From the Departments of Pathology, ^¶Biochemistry, and ^||Orthopedic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040, the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, and the ^**Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, California 92008-7208

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.

Received for publication, September 12, 2007 , and in revised form, February 14, 2008.

^* This work was supported by National Institutes of Health Grants P01-HL49373 (to L. L. R.) and T32 HL07115-28 (to J. M. B.) and American Heart Association postdoctoral fellowship 0625400U (to J. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1040. Tel.: 336-716-2821; Fax: 336-716-6279; E-mail: lrudel{at}wfubmc.edu.

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