Gadoxetic Acid-Enhanced T1 Mapping Enables Transporter-Mediated Molecular Imaging of Liver Functional Reserve

Aim: To establish and validate a quantitative transporter-mediated imaging framework based on gadoxetic acid-enhanced T1 mapping for assessing liver functional reserve (LFR) and to investigate the physiological significance of the relative change in longitudinal relaxation rate (ΔR1%) as a quantitative imaging biomarker. Methods: Female C57BL/6J mice (6-8 weeks old) representing five experimental liver conditions (control, transporter-deficient Slco1b2/Slco1a5 double-knockout, carbon tetrachloride-induced fibrosis, methionine-choline-deficient diet-induced steatohepatitis, and alcohol-associated fatty liver disease; n = 6 per group) underwent serial Gd-EOB-DTPA-enhanced T1 mapping. Quantitative ΔR1% was calculated to characterize hepatobiliary enhancement kinetics. Liver functional reserve was independently evaluated using multispectral optoacoustic tomography of indocyanine green (ICG) pharmacokinetics and serum ICG retention assays, with histopathological and hepatocellular transporter analyses performed for mechanistic validation. Longitudinal data were analyzed using restricted maximum likelihood (REML)-based mixed-effects models. Intergroup comparisons were performed using one-way ANOVA or Kruskal-Wallis tests with appropriate post hoc analyses, and associations between imaging and functional parameters were evaluated using Spearman rank correlation analysis. A two-sided p < 0.05 was considered statistically significant. Results: Five experimental liver models exhibited distinct transporter-dependent hepatobiliary enhancement patterns. The transporter-deficient knockout mice showed minimal enhancement, whereas fibrosis and steatotic liver injury models demonstrated intermediate but clearly distinguishable functional profiles. Longitudinal mixed-effects analysis identified significant effects of time, experimental group, and time-by-group interaction on ΔR1% dynamics (all p < 0.0001). Although MRI-derived ΔR1% parameters were not significantly correlated with regional optoacoustic ICG kinetics, ΔR1% area under the curve showed a strong inverse correlation with serum ICG retention at 600 s (r = -0.729, p < 0.0001), indicating that MRI-derived ΔR1% and ICG-based measurements provide complementary rather than interchangeable assessments of liver function. Histological and molecular analyses further demonstrated marked heterogeneity in fibrosis, steatosis, and hepatobiliary transporter expression across models, whereas transporter abundance alone did not consistently predict imaging-derived functional performance. Conclusions: Quantitative Gd-EOB-DTPA-enhanced T1 mapping provides a transporter-mediated imaging framework for evaluating hepatic functional reserve across mechanistically distinct liver injury models. As a normalized quantitative imaging biomarker, ΔR1% captures the integrated functional consequences of hepatobiliary transport dysfunction and complements established liver function tests. These findings support the translational potential of quantitative T1 mapping as a standardized, noninvasive approach for assessing liver functional reserve.