SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2021 |
---|---|
Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
---|---|
Enthalten in: |
Cellular and molecular gastroenterology and hepatology - 12(2021), 1 vom: 01., Seite 354-377.e3 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Deguise, Marc-Olivier [VerfasserIn] |
---|
Links: |
---|
Themen: |
Journal Article |
---|
Anmerkungen: |
Date Completed 24.01.2022 Date Revised 24.01.2022 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.jcmgh.2021.01.019 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM321060016 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM321060016 | ||
003 | DE-627 | ||
005 | 20231225175016.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231225s2021 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.jcmgh.2021.01.019 |2 doi | |
028 | 5 | 2 | |a pubmed24n1070.xml |
035 | |a (DE-627)NLM321060016 | ||
035 | |a (NLM)33545428 | ||
035 | |a (PII)S2352-345X(21)00025-4 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Deguise, Marc-Olivier |e verfasserin |4 aut | |
245 | 1 | 0 | |a SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease |
264 | 1 | |c 2021 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 24.01.2022 | ||
500 | |a Date Revised 24.01.2022 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved. | ||
520 | |a 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) | ||
520 | |a METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used | ||
520 | |a 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 | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Metabolism | |
650 | 4 | |a NAFLD | |
650 | 4 | |a NASH | |
650 | 4 | |a SMN | |
650 | 7 | |a Smn1 protein, mouse |2 NLM | |
650 | 7 | |a Survival of Motor Neuron 1 Protein |2 NLM | |
700 | 1 | |a Pileggi, Chantal |e verfasserin |4 aut | |
700 | 1 | |a De Repentigny, Yves |e verfasserin |4 aut | |
700 | 1 | |a Beauvais, Ariane |e verfasserin |4 aut | |
700 | 1 | |a Tierney, Alexandra |e verfasserin |4 aut | |
700 | 1 | |a Chehade, Lucia |e verfasserin |4 aut | |
700 | 1 | |a Michaud, Jean |e verfasserin |4 aut | |
700 | 1 | |a Llavero-Hurtado, Maica |e verfasserin |4 aut | |
700 | 1 | |a Lamont, Douglas |e verfasserin |4 aut | |
700 | 1 | |a Atrih, Abdelmadjid |e verfasserin |4 aut | |
700 | 1 | |a Wishart, Thomas M |e verfasserin |4 aut | |
700 | 1 | |a Gillingwater, Thomas H |e verfasserin |4 aut | |
700 | 1 | |a Schneider, Bernard L |e verfasserin |4 aut | |
700 | 1 | |a Harper, Mary-Ellen |e verfasserin |4 aut | |
700 | 1 | |a Parson, Simon H |e verfasserin |4 aut | |
700 | 1 | |a Kothary, Rashmi |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Cellular and molecular gastroenterology and hepatology |d 2015 |g 12(2021), 1 vom: 01., Seite 354-377.e3 |w (DE-627)NLM246683694 |x 2352-345X |7 nnns |
773 | 1 | 8 | |g volume:12 |g year:2021 |g number:1 |g day:01 |g pages:354-377.e3 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jcmgh.2021.01.019 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 12 |j 2021 |e 1 |b 01 |h 354-377.e3 |