Development of a mouse model for postresectional liver failure

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Background Postresectional liver failure (PLF) is a dreaded complication after extended liver resection. Post-operative hyperbilirubinemia suggests that impaired hepatobiliary transport with intrahepatic accumulation of harmful cholephiles plays an etiological role. Bile salts serve dual roles as signaling molecules engaged in liver regeneration after partial hepatectomy (PH) and biological detergents. Aim In this study we tested the hypothesis that excessive accumulation of bile salts in the regenerating liver results in PLF. Methods Twelve weeks old male C57BL6/J mice were subjected to 70% PH and post-operatively challenged with a diet supplemented with cholic acid (CA, 0.5 or 1.0%; n=5-6 per group) or a control diet. After 48 hours mice were sacrificed, and liver injury, secretory function, and regenerative indices were assessed. Results Mice fed a 1.0% CA diet displayed more pronounced weight loss following PH and had a deranged post-operative glucose course. Liver injury (aminotransferase elevations) and impaired hepatobiliary transport function (hyperbilirubinemia) were apparent in the group fed a 1.0% CA diet, but not in animals fed a 0.5% CA diet. No differences in liver mass recovery were observed among groups. However, the percentage of hepatocytes staining positive for the proliferation marker Ki-67 were reduced in mice receiving a 1.0% CA diet relative to animals fed a 0.5% CA diet. PH-induced expression of key factors involved in cell cycle progression ( e . g. Foxm1b, Cdc25b ) was abrogated in the 1.0% CA group. Conclusion A postresectional challenge with a 1.0% CA diet induces signs of liver injury and defective liver regeneration. A longer duration of the dietary challenge and/or secondary hits may further improve the model. Once validated, it can be used to evaluate pharmaceutical strategies to prevent or treat PLF.

Authors 8

1. Kim M.C. van Mierlo

   Maastricht University

   Affiliation as printed

   Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

2. C. Van Himbeeck

   Maastricht University

   Affiliation as printed

   Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

3. Valérie Lebrun

   UCLouvain

   Affiliation as printed

   Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

4. Peter L. M. Jansen

   Maastricht University

   Affiliation as printed

   Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

5. Cornelius H.C. Dejong

   Maastricht University

   Affiliation as printed

   Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

6. Isabelle Anne Leclercq

   UCLouvain

   Affiliation as printed

   Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

7. Steven W.M. Olde Damink Aachen Department of General, Visceral and Transplantation Surgery

   Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany

   Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands

8. Frank G. Schaap corresponding Aachen Department of General, Visceral and Transplantation Surgery

   Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany

   Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands