title: PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis.
abstract: We report the engineering and characterization of paraoxonase-3 knockout mice (Pon3KO). The mice were generally healthy but exhibited quantitative alterations in bile acid metabolism and a 37% increased body weight compared to the wild-type mice on a high fat diet. PON3 was enriched in the mitochondria-associated membrane fraction of hepatocytes. PON3 deficiency resulted in impaired mitochondrial respiration, increased mitochondrial superoxide levels, and increased hepatic expression of inflammatory genes. PON3 deficiency did not influence atherosclerosis development on an apolipoprotein E null hyperlipidemic background, but it did lead to a significant 60% increase in atherosclerotic lesion size in Pon3KO mice on the C57BL/6J background when fed a cholate-cholesterol diet. On the diet, the Pon3KO had significantly increased plasma intermediate-density lipoprotein/LDL cholesterol and bile acid levels. They also exhibited significantly elevated levels of hepatotoxicity markers in circulation, a 58% increase in gallstone weight, a 40% increase in hepatic cholesterol level, and increased mortality. Furthermore, Pon3KO mice exhibited decreased hepatic bile acid synthesis and decreased bile acid levels in the small intestine compared with wild-type mice. Our study suggests a role for PON3 in the metabolism of lipid and bile acid as well as protection against atherosclerosis, gallstone disease, and obesity.
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland dshih@mednet.ucla.edu.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Yu
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Nassim
authors.initials: N
authors.lastname: Dali-Youcef
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Champion
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Asokan
authors.initials: A
authors.lastname: Devarajan
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Zhang
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Carole
authors.initials: C
authors.lastname: Jamey
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.affiliation: *Division of Cardiology, Department of Medicine, Department of Microbiology, Immunology, and Molecular Genetics, Department of Human Genetics, Department of Molecular and Medical Pharmacology, and Department of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA; IGBMC, Illkirch and Hôpitaux Universitaires de Strasbourg, and **Laboratoire de Toxicologie, Universitaires de Strasbourg, Strasbourg, France; Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, St. Louis University School of Medicine, St. Louis, Missouri, USA; University of Alberta, Edmonton, Alberta, Canada; and Laboratory for Integrative and Systems Physiology, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D019826:Cholic Acid / Q000008:administration & dosage; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D042882:Gallstones / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000209:etiology / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D001647:Bile Acids and Salts; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D018836:Inflammation Mediators; D015850:Interleukin-6; D043303:Aryldialkylphosphatase; C560866:PON3 protein, mouse; D019826:Cholic Acid
keywords: bile acid; cholesterol; hyperlipidemia; mitochondria; mitochondria-associated membrane