Characterization of hepatic fatty acids using Magnetic Resonance Spectroscopy for the assessment of treatment response to Metformin in an eNOS -/- mouse model of metabolic NAFLD-NASH.

Non-Alcoholic Fatty Liver Disease (NAFLD) is the leading cause of chronic liver disease worldwide. Liver biopsy remains the gold-standard for diagnosis and staging of disease. There is a clinical need for non-invasive diagnostic tools for risk stratification, follow-up and monitoring treatment response which are currently lacking, as well as preclinical models that recapitulate the etiology of the human condition. We have characterized the progression of NAFLD in eNOS -/- mice fed high fat diet (HFD) using non-invasive Dixon-based Magnetic Resonance Imaging and single voxel STEAM Spectroscopy-based protocols to measure liver fat fraction at 3T. After 8 weeks of diet intervention, eNOS -/- mice exhibited significant accumulation of intraabdominal and liver fat compared with control mice. Liver fat fraction measured by 1 H-MRS in vivo showed a good correlation with the NAFLD Activity Score (NAS) measured by histology. Treatment of HFD-fed NOS3 -/- mice with metformin showed significantly reduced liver fat fraction and altered hepatic lipidomic profile compared to untreated mice. Our results show the potential of in-vivo liver MRI and 1 H-MRS to non-invasively diagnose and stage the progression of NAFLD and monitor treatment response in an eNOS -/- murine model which represents the classic NAFLD phenotype associated with metabolic syndrome.