SMN depleted mice offer a robust and rapid onset model of non-alcoholic fatty liver disease

Abstract Background & aims Non-alcoholic fatty liver disease is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current pre-clinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of 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 non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether Smn2B/- mice display typical features of NAFLD/non-alcoholic steatohepatitis (NASH). Methods Biochemical, histological, electron microscopy, proteomic, and high-resolution respirometry were used. Results The Smn2B/- mice develop microvesicular steatohepatitis within two weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histological 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 IGF-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid (NEFA) 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 due to their associated neurological condition (Spinal Muscular Atrophy) and develop hypoglycemia. Conclusion 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.