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.

Abstract

BackgroundTreatments 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.PurposeThis 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 TypePreclinical.Animal ModelThis 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/SequenceThis 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).AssessmentMRI 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 TestsTwo‐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.ResultsCDAHFD 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 ConclusionsMRI‐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 Evidence1Technical Efficacy Stage2