SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease

Abstract

The Smn 2B/mice, a mouse model with reduced level of SMN protein, represent a good model of microvesicular steatohepatitis. They offer a reliable, low-cost, early-onset model to identify molecular players in the pathogenesis of NAFLD in both the adult and pediatric populations. 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 (Smn 2B/mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn 2B/mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn 2B/mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH). METHODS: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.

Metabolic Dysfunction in Spinal Muscular Atrophy

“…More particularly, severe mouse models had less fat in their liver, while models of milder severity had an accumulation of triglycerides (TGs) in their liver [ 31 ]. Of these models, the Smn 2B/− mice invariably developed non-alcoholic fatty liver disease (NAFLD) and dyslipidemia while on normal chow [ 30 , 31 ]. Interestingly, only minor changes were identified in fat classes and chain length in SMA disease-relevant tissues such as the spinal cord and the muscle in pre-clinical models, pointing to the possibility that this may be restricted to the liver or the metabolic organs [ 31 ].…”

“…The cause of fatty liver and dyslipidemia in SMA remains unknown. Despite showing wide proteomic changes in mitochondrial health and function, mitochondrial dysfunction is unlikely, as the isolated hepatic mitochondria from Smn 2B/− mice function better than control [ 30 ]. This was suggested to be compensatory to the high TG content in the Smn 2B/− livers in order to enhance clearance and restore homeostasis.…”

“…Interestingly, a recent study showed that Taiwanese (Smn ∆7/∆7 ;SMN2 +/+ ) mice have a global shift in their respiratory exchange ratio, hence relying more heavily on β-oxidation [ 56 ]. The Smn 2B/− hepatic mitochondria produce more reactive oxygen species, leading to liver damage and functional deficit (protein production, hemostasis, complement, iron metabolism, insulin-like growth factor 1 (IGF1) pathway) [ 30 ]. Noteworthy, microsomal oxidation, an alternative oxidative pathway turned on upon β-oxidation overload, produces dicarboxylic acids [ 99 ].…”

“…However, accumulating evidence has challenged this traditional paradigm. SMN depletion is also detrimental to other tissues and organs, affecting whole-body physiology [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Most recently, metabolic and endocrine organs have also been reported to show altered function in SMA.…”

“…Early research focused on lipid disturbances in different forms of spinal muscular atrophies [ 36 , 37 , 38 , 39 ]. Several new studies have highlighted numerous metabolic alterations in SMA patients and animal models of the disease [ 30 , 31 , 40 , 41 ]. However, it should be noted that a clear mechanism linking SMN depletion and the various metabolic abnormalities is currently lacking.…”