title: Acute sterol o-acyltransferase 2 (SOAT2) knockdown rapidly mobilizes hepatic cholesterol for fecal excretion.
abstract: The primary risk factor for atherosclerotic cardiovascular disease is LDL cholesterol, which can be reduced by increasing cholesterol excretion from the body. Fecal cholesterol excretion can be driven by a hepatobiliary as well as a non-biliary pathway known as transintestinal cholesterol efflux (TICE). We previously showed that chronic knockdown of the hepatic cholesterol esterifying enzyme sterol O-acyltransferase 2 (SOAT2) increased fecal cholesterol loss via TICE. To elucidate the initial events that stimulate TICE, C57Bl/6 mice were fed a high cholesterol diet to induce hepatic cholesterol accumulation and were then treated for 1 or 2 weeks with an antisense oligonucleotide targeting SOAT2. Within 2 weeks of hepatic SOAT2 knockdown (SOAT2HKD), the concentration of cholesteryl ester in the liver was reduced by 70% without a reciprocal increase in hepatic free cholesterol. The rapid mobilization of hepatic cholesterol stores resulted in a ∼ 2-fold increase in fecal neutral sterol loss but no change in biliary cholesterol concentration. Acute SOAT2HKD increased plasma cholesterol carried primarily in lipoproteins enriched in apoB and apoE. Collectively, our data suggest that acutely reducing SOAT2 causes hepatic cholesterol to be swiftly mobilized and packaged onto nascent lipoproteins that feed cholesterol into the TICE pathway for fecal excretion.
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Marshall
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Foundation - Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Gromovsky
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Kelley
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Davis
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Martha D
authors.initials: MD
authors.lastname: Wilson
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, California, United States of America.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America; Department of Cellular and Molecular Medicine, Cleveland Clinic Foundation - Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America; Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat; D005243:Feces / Q000737:chemistry*; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000097587:Sterol O-Acyltransferase 2
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; D002784:Cholesterol; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008074:Lipoproteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2