SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary
Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21000254 |
| _version_ | 1831757394244272128 |
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| author | Marc-Olivier Deguise Chantal Pileggi Yves De Repentigny Ariane Beauvais Alexandra Tierney Lucia Chehade Jean Michaud Maica Llavero-Hurtado Douglas Lamont Abdelmadjid Atrih Thomas M. Wishart Thomas H. Gillingwater Bernard L. Schneider Mary-Ellen Harper Simon H. Parson Rashmi Kothary |
| author_facet | Marc-Olivier Deguise Chantal Pileggi Yves De Repentigny Ariane Beauvais Alexandra Tierney Lucia Chehade Jean Michaud Maica Llavero-Hurtado Douglas Lamont Abdelmadjid Atrih Thomas M. Wishart Thomas H. Gillingwater Bernard L. Schneider Mary-Ellen Harper Simon H. Parson Rashmi Kothary |
| author_sort | Marc-Olivier Deguise |
| collection | DOAJ |
| description | Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH). Methods: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used. Results: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia. Conclusions: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations. |
| first_indexed | 2024-12-22T00:30:37Z |
| format | Article |
| id | doaj.art-17bff1dec6fd49edbbb066b4aa9e5172 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-22T00:30:37Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-17bff1dec6fd49edbbb066b4aa9e51722022-12-21T18:44:57ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-01121354377.e3SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummaryMarc-Olivier Deguise0Chantal Pileggi1Yves De Repentigny2Ariane Beauvais3Alexandra Tierney4Lucia Chehade5Jean Michaud6Maica Llavero-Hurtado7Douglas Lamont8Abdelmadjid Atrih9Thomas M. Wishart10Thomas H. Gillingwater11Bernard L. Schneider12Mary-Ellen Harper13Simon H. Parson14Rashmi Kothary15Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, CanadaDepartment of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, CanadaDepartment of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, CanadaEuan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United KingdomFingerPrints Proteomics Facility, University of Dundee, Dundee, United KingdomFingerPrints Proteomics Facility, University of Dundee, Dundee, United KingdomEuan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; The Roslin Institute, Royal (Dick) School of Veterinary Studies, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United KingdomEuan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, United KingdomBrain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Bertarelli Foundation Gene Therapy Platform, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Geneva, SwitzerlandDepartment of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, CanadaEuan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom; Institute of Medical Sciences, University of Aberdeen, Aberdeen, United KingdomRegenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Correspondence Address correspondence to: Rashmi Kothary, PhD, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. fax: (613) 737-8803.Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn2B/- mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn2B/- mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn2B/- mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH). Methods: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used. Results: The Smn2B/- mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn2B/- mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia. Conclusions: The Smn2B/- mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.http://www.sciencedirect.com/science/article/pii/S2352345X21000254SMNNAFLDNASHMetabolism |
| spellingShingle | Marc-Olivier Deguise Chantal Pileggi Yves De Repentigny Ariane Beauvais Alexandra Tierney Lucia Chehade Jean Michaud Maica Llavero-Hurtado Douglas Lamont Abdelmadjid Atrih Thomas M. Wishart Thomas H. Gillingwater Bernard L. Schneider Mary-Ellen Harper Simon H. Parson Rashmi Kothary SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary Cellular and Molecular Gastroenterology and Hepatology SMN NAFLD NASH Metabolism |
| title | SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary |
| title_full | SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary |
| title_fullStr | SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary |
| title_full_unstemmed | SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary |
| title_short | SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver DiseaseSummary |
| title_sort | smn depleted mice offer a robust and rapid onset model of nonalcoholic fatty liver diseasesummary |
| topic | SMN NAFLD NASH Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21000254 |
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