title: Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice.
abstract: Mitochondrial dysfunction is associated with many human diseases and results from mismatch of damage and repair over the life of the organelle. PARK2 is a ubiquitin E3 ligase that regulates mitophagy, a repair mechanism that selectively degrades damaged mitochondria. Deletion of PARK2 in multiple in vivo models results in susceptibility to stress-induced mitochondrial and cellular dysfunction. Surprisingly, Park2 knockout (KO) mice are protected from nutritional stress and do not develop obesity, hepatic steatosis or insulin resistance when fed a high-fat diet (HFD). However, these phenomena are casually related and the physiological basis for this phenotype is unknown. We therefore undertook a series of acute HFD studies to more completely understand the physiology of Park2 KO during nutritional stress. We find that intestinal lipid absorption is impaired in Park2 KO mice as evidenced by increased fecal lipids and reduced plasma triglycerides after intragastric fat challenge. Park2 KO mice developed hepatic steatosis in response to intravenous lipid infusion as well as during incubation of primary hepatocytes with fatty acids, suggesting that hepatic protection from nutritional stress was secondary to changes in energy balance due to altered intestinal triglyceride absorption. Park2 KO mice showed reduced adiposity after 1-wk HFD, as well as improved hepatic and peripheral insulin sensitivity. These studies suggest that changes in intestinal lipid absorption may play a primary role in protection from nutritional stress in Park2 KO mice by preventing HFD-induced weight gain and highlight the need for tissue-specific models to address the role of PARK2 during metabolic stress.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Diana K
authors.initials: DK
authors.lastname: Costa
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Brydie R
authors.initials: BR
authors.lastname: Huckestein
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Lia R
authors.initials: LR
authors.lastname: Edmunds
authors.affiliation: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Max C
authors.initials: MC
authors.lastname: Petersen
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Ali
authors.initials: A
authors.lastname: Nasiri
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Gina M
authors.initials: GM
authors.lastname: Butrico
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Abudukadier
authors.initials: A
authors.lastname: Abulizi
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Harmon
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Canying
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Mantell
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hartman
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: João-Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut; The Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut; and.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania jurczakm@pitt.edu.
authors.forename: Michael J
authors.identifier: http://orcid.org/0000-0002-6335-6915
authors.initials: MJ
authors.lastname: Jurczak
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics*; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005227:Fatty Acids / Q000494:pharmacology; D005234:Fatty Liver / Q000235:genetics; D005243:Feces / Q000737:chemistry; D007262:Infusions, Intravenous; D007333:Insulin Resistance / Q000235:genetics*; D007408:Intestinal Absorption / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000032:analysis / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D015430:Weight Gain / Q000235:genetics
chemical_list: D005227:Fatty Acids; D008055:Lipids; D014280:Triglycerides; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: PARK2; insulin resistance; lipid absorption; liver; mitophagy; obesity; small intestine