TY - JOUR
T1 - SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease
AU - Deguise, Marc-Olivier
AU - Pileggi, Chantal
AU - De Repentigny, Yves
AU - Beauvais, Ariane
AU - Tierney, Alexandra
AU - Chehade, Lucia
AU - Michaud, Jean
AU - Llavero-Hurtado, Maica
AU - Lamont, Douglas
AU - Atrih, Abdelmadjid
AU - Wishart, Thomas M
AU - Gillingwater, Thomas H
AU - Schneider, Bernard L
AU - Harper, Mary-Ellen
AU - Parson, Simon H
AU - Kothary, Rashmi
N1 - Acknowledgments
The authors thank Eva Szunyogova, Sabrina Gagnon, My Tran Trung, andRebecca Yaworski, the Vanderbilt Mouse Metabolic Phenotyping Center, and the University of Massachusetts Medical School National Mouse Metabolic Phenotyping Center (MMPC) for assistance with experiments. They also thank Dr Lyndsay Murray for providing some tissues for the present study.
PY - 2021
Y1 - 2021
N2 - 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 nonesterified 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.
AB - 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 nonesterified 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.
KW - SMN
KW - NAFLD
KW - NASH
KW - Metabolism
U2 - 10.1016/j.jcmgh.2021.01.019
DO - 10.1016/j.jcmgh.2021.01.019
M3 - Article
C2 - 33545428
VL - 12
SP - 354
EP - 377
JO - CMGH Cellular and Molecular Gastroenterology and Hepatology
JF - CMGH Cellular and Molecular Gastroenterology and Hepatology
SN - 2352-345X
IS - 1
ER -