title: Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.
abstract: An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.
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: Stephanie M
authors.initials: SM
authors.lastname: Marshall
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: Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Allison L
authors.initials: AL
authors.lastname: McDaniel
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; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020320:Oligoribonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D020320:Oligoribonucleotides, Antisense; D011973:Receptors, LDL; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol