Augmented Wnt signaling as a therapeutic tool to prevent ischemia/reperfusion injury in liver: Preclinical studies in a mouse model

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
Bowen LiuKarl G Sylvester

Abstract

The Wnt signaling pathway has established biological roles in liver development, regeneration, and carcinogenesis. Given the common need for cellular energy utilization in each of these processes, we hypothesized that Wnt signaling would directly regulate hepatocyte mitochondrial function. Mice were engineered to overexpress Wnt1 in hepatocytes under the control of a tetracycline analogue. Wnt1 and wild-type mice underwent ischemia/reperfusion injury (IRI) to induce oxidative mitochondrial injury. Alpha mouse liver 12 (AML12) hepatocytes were exposed to Wnt agonists for in vitro hypoxia/reoxygenation (H-R) experiments. We observed stabilized mitochondrial membrane potential and reduced levels of hepatocyte apoptosis involving the mitochondrial pathway in Wnt1 mice compared to controls following IRI. Wnt1 mice also demonstrated increased mitochondrial DNA copy number, as well as an increased tricarboxylic acid cycle activity and adenosine triphosphate levels indicating that mitochondrial function is preserved by Wnt1 overexpression following IRI. AML12 cells treated by Wnt3a or the glycogen synthase kinase 3β inhibitor LiCl exposed to H-R demonstrated decreased reactive oxygen species and reduced apoptosis compared to controls. ...Continue Reading

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Citations

Apr 4, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Samer TohmeAllan Tsung
Feb 18, 2017·Dose-response : a Publication of International Hormesis Society·Vivekkumar P DadhaniaHarihara M Mehendale

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