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PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis.
Journal article

PON3 knockout mice are susceptible to obesity, gallstone formation, and atherosclerosis.

  • Shih DM *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.
  • Yu JM *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.
  • Vergnes L *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.
  • Dali-Youcef N *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.
  • Champion MD *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.
  • Devarajan A *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.
  • Zhang P *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.
  • Castellani LW *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.
  • Brindley DN *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.
  • Jamey C *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.
  • Auwerx J *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.
  • Reddy ST *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.
  • Ford DA *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.
  • Reue K *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.
  • Lusis AJ *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.
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  • 2014-12-06
Published in:
  • FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - 2015
bile acid
cholesterol
hyperlipidemia
mitochondria
mitochondria-associated membrane
Animals
Apolipoproteins E
Aryldialkylphosphatase
Atherosclerosis
Bile Acids and Salts
Chemokine CCL2
Cholesterol, Dietary
Cholic Acid
Diet
Disease Models, Animal
Female
Gallstones
Gene Expression
Genetic Predisposition to Disease
Inflammation Mediators
Interleukin-6
Intestine, Small
Kidney
Lipid Metabolism
Liver
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Liver
Obesity
English 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.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/156049
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