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Publication
SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty
Liver Disease.
Authors Deguise MO, Pileggi C, De Repentigny Y, Beauvais A, Tierney A, Chehade L,
Michaud J, Llavero-Hurtado M, Lamont D, Atrih A, Wishart TM, Gillingwater TH,
Schneider BL, Harper ME, Parson SH, Kothary R
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Cellular and molecular gastroenterology and hepatology
Year 2021
Date Published
Volume : Pages 12 : 354 - 377.e3
PubMed Reference 33545428
Abstract 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)., Biochemical, histologic, electron microscopy,
proteomic, and high-resolution respirometry were used., 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 ß-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., 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.




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