title: Impaired autophagy induces chronic atrophic pancreatitis in mice via sex- and nutrition-dependent processes.
abstract: OBJECTIVE
  Little is known about the mechanisms of the progressive tissue destruction, inflammation, and fibrosis that occur during development of chronic pancreatitis. Autophagy is involved in multiple degenerative and inflammatory diseases, including pancreatitis, and requires the protein autophagy related 5 (ATG5). We created mice with defects in autophagy to determine its role in pancreatitis.
  
  
  METHODS
  We created mice with pancreas-specific disruption of Atg5 (Ptf1aCreex1;Atg5F/F mice) and compared them to control mice. Pancreata were collected and histology, immunohistochemistry, transcriptome, and metabolome analyses were performed. ATG5-deficient mice were placed on diets containing 25% palm oil and compared with those on a standard diet. Another set of mice received the antioxidant N-acetylcysteine. Pancreatic tissues were collected from 8 patients with chronic pancreatitis (CP) and compared with pancreata from ATG5-deficient mice.
  
  
  RESULTS
  Mice with pancreas-specific disruption of Atg5 developed atrophic CP, independent of β-cell function; a greater proportion of male mice developed CP than female mice. Pancreata from ATG5-deficient mice had signs of inflammation, necrosis, acinar-to-ductal metaplasia, and acinar-cell hypertrophy; this led to tissue atrophy and degeneration. Based on transcriptome and metabolome analyses, ATG5-deficient mice produced higher levels of reactive oxygen species than control mice, and had insufficient activation of glutamate-dependent metabolism. Pancreata from these mice had reduced autophagy, increased levels of p62, and increases in endoplasmic reticulum stress and mitochondrial damage, compared with tissues from control mice; p62 signaling to Nqo1 and p53 was also activated. Dietary antioxidants, especially in combination with palm oil-derived fatty acids, blocked progression to CP and pancreatic acinar atrophy. Tissues from patients with CP had many histologic similarities to those from ATG5-deficient mice.
  
  
  CONCLUSIONS
  Mice with pancreas-specific disruption of Atg5 develop a form of CP similar to that of humans. CP development appears to involve defects in autophagy, glutamate-dependent metabolism, and increased production of reactive oxygen species. These mice might be used to identify therapeutic targets for CP.
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Kalliope N
authors.initials: KN
authors.lastname: Diakopoulos
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Wörmann
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Liang
authors.initials: L
authors.lastname: Song
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Institut für Klinische Chemie und Pathobiochemie, Bereich Pathologische Biochemie, Otto-von-Guericke-Universität Magdeburg Medizinische Fakultät, Magdeburg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Schild
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Artati
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.affiliation: Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wartmann
authors.affiliation: Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Institut für Molekulare Toxikologie und Pharmakologie, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Yashar
authors.initials: Y
authors.lastname: Kabiri
authors.affiliation: Institut für Molekulare Toxikologie und Pharmakologie, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.affiliation: Klinik für Chirurgie Bereich Experimentelle Operative Medizin, Universitätsklinikum Magdeburg, Magdeburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Halangk
authors.affiliation: Chirurgische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ihsan Ekin
authors.initials: IE
authors.lastname: Demir
authors.affiliation: Else Kröner-Fresenius-Zentrum, Paediatric Nutritional Medicine, Technische Universität München, Freising, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pilsak
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christos S
authors.initials: CS
authors.lastname: Mantzoros
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Jörg M
authors.initials: JM
authors.lastname: Steiner
authors.affiliation: Department of Surgery, School of Medicine, Koc University, Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Else Kröner-Fresenius-Zentrum, Paediatric Nutritional Medicine, Technische Universität München, Freising, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Centre, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. Electronic address: hana.alguel@lrz.tum.de.
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001284:Atrophy; D001343:Autophagy / Q000235:genetics* / Q000276:immunology; D000071187:Autophagy-Related Protein 5; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D000073878:Palm Oil; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D010938:Plant Oils / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D012737:Sex Factors; D016159:Tumor Suppressor Protein p53 / Q000276:immunology / Q000378:metabolism
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D016166:Free Radical Scavengers; D008869:Microtubule-Associated Proteins; D010938:Plant Oils; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000073878:Palm Oil; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D000111:Acetylcysteine
keywords: Autophagosome; Lipidation; Pathogenesis; Signal Transduction