Characterization of Hepatic Fatty Acids Using Magnetic Resonance Spectroscopy for the Assessment of Treatment Response to Metformin in an Enos−/− Mouse Model of Metabolic Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Nonalcoholic 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 noninvasive diagnostic tools for risk stratification, follow-up, and monitoring treatment response that 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 a high fat diet (HFD) using noninvasive Dixon-based magnetic resonance imaging and single voxel STEAM spectroscopy-based protocols to measure liver fat fraction at 3 T. After 8 weeks of diet intervention, eNOS−/− mice exhibited significant accumulation of intra-abdominal and liver fat compared with control mice. Liver fat fraction measured by 1H-MRS in vivo showed a good correlation with the NAFLD activity score measured by histology. Treatment of HFD-fed NOS3−/− mice with metformin showed significantly reduced liver fat fraction and altered hepatic lipidomic profile compared with untreated mice. Our results show the potential of in vivo liver MRI and 1H-MRS to noninvasively diagnose and stage the progression of NAFLD and to monitor treatment response in an eNOS−/− murine model that represents the classic NAFLD phenotype associated with metabolic syndrome. © 2023 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.