Impact of hepatic perfusion on lobular and lobar distribution of test compound metabolism in rats

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Patients subjected to extended liver resection ((e)PHx) have a high risk to experience postoperative liver dysfunction or even liver failure, especially in case of preexisting liver disease. Our research group QuaLiPerF aims to enhance the understanding of the quantitative and spatial relationship between hepatic perfusion and function in healthy, steatotic and regenerating livers after surgery using a systems medicine approach. This project will focus on assessing the impact of perfusion perturbation and perfusion impairment on loss and recovery of liver function. We hypothesize that spatial inhomogeneity of perfusion matches the functional performance of the hepatocytes and their proliferation during regeneration. It is our aim to assess the impact of hepatic perfusion on test compound metabolism in normal, steatotic and regenerating livers by a) spatially resolved quantification of hepatic perfusion and steatosis on the lobular and lobar scale,b) exploring the capacity and spatial distribution of test compound metabolism in relation to hepatocyte proliferation.To reach this goal, we are going to investigate liver perfusion impairments on multiple scales using three different approaches of perfusion perturbation in the rat model: hepatic steatosis, portal vein ligation, and liver resection. Animals will be subjected to detailed assessment of hepatic hemodynamics and microcirculation using side-stream dark field imaging and an optical sensor revealing the tissue oxygenation. Probing multiple liver lobes will reveal the heterogeneity of hepatic perfusion.Test compound metabolism is used for scale spanning assessment of hepatic function. We will perform pharmacokinetic studies after applying five different test compounds. We will analyze metabolism of these drugs by determination of the corresponding CYP enzyme activity, measurement of protein and mRNA levels and determination of zonal expression in tissue samples obtained from different liver lobes to account for heterogeneity. Liver regeneration will be assessed immediately after surgery and within the first postoperative week by addressing liver-to-body-weight ratios, volume and functional recovery as well as proliferation of hepatocytes.These results will be compared to detailed MRI assessment of liver volume, perfusion and function. Our results will be complementary to investigations of the carbohydrate/lipid metabolism and a detailed gene expression analysis. Thus, a comprehensive network of metabolic control assessment as a function of liver perfusion will be generated.All experimental data together with corresponding clinical data will serve as input for the integrated computational models needed for spatially resolved prediction of regeneration and functional recovery of the future liver remnant after liver surgery. As a result, prediction of function and risk stratification for patients undergoing (e)PHX will be improved.