title: Sterol O-Acyltransferase 2-Driven Cholesterol Esterification Opposes Liver X Receptor-Stimulated Fecal Neutral Sterol Loss.
abstract: Statin drugs have proven a successful and relatively safe therapy for the treatment of atherosclerotic cardiovascular disease (CVD). However, even with the substantial low-density lipoprotein (LDL) cholesterol lowering achieved with statin treatment, CVD remains the top cause of death in developed countries. Selective inhibitors of the cholesterol esterifying enzyme sterol-O acyltransferase 2 (SOAT2) hold great promise as effective CVD therapeutics. In mouse models, previous work has demonstrated that either antisense oligonucleotide (ASO) or small molecule inhibitors of SOAT2 can effectively reduce CVD progression, and even promote regression of established CVD. Although it is well known that SOAT2-driven cholesterol esterification can alter both the packaging and retention of atherogenic apoB-containing lipoproteins, here we set out to determine whether SOAT2-driven cholesterol esterification can also impact basal and liver X receptor (LXR)-stimulated fecal neutral sterol loss. These studies demonstrate that SOAT2 is a negative regulator of LXR-stimulated fecal neutral sterol loss in mice.
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.|Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Manya
authors.initials: M
authors.lastname: Warrier
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Kanwardeep
authors.initials: K
authors.lastname: Bura
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kelley
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Martha D
authors.initials: MD
authors.lastname: Wilson
authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA. brownm5@ccf.org.|Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. brownm5@ccf.org.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D004951:Esterification; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D008077:Lipoproteins, LDL / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000235:genetics*; D013261:Sterols / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D002784:Cholesterol; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D016376:Oligonucleotides, Antisense; D057093:Orphan Nuclear Receptors; D002785:Sterol O-Acyltransferase; D013261:Sterols; D000097587:Sterol O-Acyltransferase 2
keywords: Atherosclerosis; Cholesterol; Esterification; Intestine