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Published on: April 2, 2017
Akt: A Therapeutic Target in Hepatic Ischemia-Reperfusion Injury
Stephen M Covington1, Laura D Bauler2, Luis H Toledo-Pereyra2
1a Michigan State University College of Osteopathic Medicine , East Lansing, Michigan , USA.
Background:
Liver transplantation is the second most common transplant procedure in the United States. A leading cause of post-transplantation organ dysfunction is I/R injury. During I/R injury, the serine/threonine kinase Akt is activated, stimulating downstream mediators to promote cellular survival. Due to the cellular effects of Akt, therapeutic manipulation of the Akt pathway can help reduce cellular damage during hepatic I/R that occurs during liver transplantation.
Objective:
A full description of therapeutic options available that target Akt to reduce hepatic I/R injury has not been addressed within the literature. The purpose of this review is to illuminate advances in the manipulation of Akt that can be used to therapeutically target I/R injury in the liver.
Methods:
An in depth literature review was performed using the Scopus and PubMed databases. A total of 75 published articles were utilized for this manuscript. Terminology searched includes a combination of "hepatic ischemia/reperfusion injury", "Akt/PKB", "preconditioning" and "postconditioning."
Results:
Four principal methods that reduce I/R injury include hepatic pre- and postconditioning, pharmacological intervention and future miRNA/gene therapy. Discussed therapies used serum alanine aminotransferase levels, liver histology and phosphorylation of downstream mediators to confirm the Akt protective effect.
Conclusion:
The activation of Akt from the reviewed therapies has resulted in predictable reduction in hepatocyte damage using the previously mentioned measurements. In a clinical setting, these therapies could potentially be used in combination to achieve better outcomes in hepatic transplant patients. Evidence supporting reduced I/R injury through Akt activation warrants further studies in human clinical trials.
Insights
Therapeutic manipulation of the Akt pathway can reduce liver damage from ischemia/reperfusion (I/R) injury during transplantation. Activating Akt shows promise in protecting hepatocytes and warrants further clinical trials.
Area of Science:
- Transplantation immunology
- Molecular biology
- Hepatology
Background:
- Liver transplantation is common, but ischemia/reperfusion (I/R) injury causes significant post-transplant dysfunction.
- The serine/threonine kinase Akt is activated during I/R injury and promotes cellular survival.
- Targeting the Akt pathway offers a potential strategy to mitigate hepatic I/R injury.
Purpose of the Study:
- This review comprehensively examines therapeutic strategies targeting the Akt pathway to reduce hepatic I/R injury.
- It aims to highlight recent advances in manipulating Akt for therapeutic benefit in liver transplantation.
Main Methods:
- An extensive literature review was conducted using Scopus and PubMed databases.
- Seventy-five articles were analyzed, combining search terms like "hepatic ischemia/reperfusion injury" and "Akt/PKB."
- Key concepts explored included preconditioning, postconditioning, and pharmacological interventions.
Main Results:
- Four primary methods to reduce I/R injury were identified: hepatic preconditioning, postconditioning, pharmacological interventions, and miRNA/gene therapy.
- Therapeutic efficacy was confirmed by reductions in serum alanine aminotransferase levels and improved liver histology.
- Phosphorylation of downstream mediators validated the protective effects mediated by Akt activation.
Conclusions:
- Akt activation consistently reduces hepatocyte damage, as evidenced by biochemical and histological markers.
- Combining these Akt-targeting therapies may improve outcomes for liver transplant recipients.
- Further clinical trials are needed to validate these findings in human subjects.
