Evaluation of a PEGylated Fibroblast Growth Factor 21 Variant Using Novel Preclinical Magnetic Resonance Imaging and Magnetic Resonance Elastography in a Mouse Model of Nonalcoholic Steatohepatitis

Background Treatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI-HFF) and magnetic resonance elastography (MRE-SS), respectively, are biomarkers for hepatic steatosis and fibrosis. Purpose This study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]-FGF21v) on MRI-HFF and MRE-SS in a NASH mouse model. Study Type Preclinical. Animal Model This study included a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) model and 6-week-old, male C57BL/6J mice (N = 78). Field Strength/Sequence This study was performed using: 3T: gradient-echo two-point Dixon and spin-echo (SE) echo-planar imaging elastography (200 Hz) and 7T: SE two-point Dixon and SE elastography (200 Hz). Assessment MRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG-FGF21v dosing (baseline), and after PEG-FGF21v treatment (WK4/8). Regions of interest for MRI-HFF and MRE-SS were delineated by J.L. and H.T. (>5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and H&E staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured. Statistical Tests Two-tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE-SS at WK8, posterior means, and 95% credible intervals were presented. Results CDAHFD significantly increased baseline MRI-HFF (3T: 21.97% +/- 0.29%; 7T: 40.12% +/- 0.35%) and MRE-SS (3T: 1.25 +/- 0.02; 7T: 1.78 +/- 0.06 kPa) vs. CD (3T: 3.45% +/- 0.7%; 7T: 12.06% +/- 1.4% and 3T: 1.01 +/- 0.02; 7T: 0.89 +/- 0.06 kPa). At 7T, PEG-FGF21v significantly decreased MRI-HFF (WK4: 28.97% +/- 1.22%; WK8: 20.93% +/- 1.15%) and MRE-SS (WK4: 1.57 +/- 0.04; WK8: 1.36 +/- 0.05 kPa) vs. untreated (WK4: 36.36% +/- 0.62%; WK8: 30.58% +/- 0.81% and WK4: 2.03 +/- 0.06; WK8: 2.01 +/- 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (R-DI) were -68% (-90%, -44%; 3T) and -64% (-78%, -52%; 7T). MRI-HFF was significantly correlated with H&E (3T, r = 0.93; 7T, r = 0.94) and TGs (both, r = 0.92). Data Conclusions MRI-HFF and MRE-SS showed PEG-FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data. Level of Evidence 1 Technical Efficacy Stage 2