Liver-Directed A20 Gene Therapy Restores the Regenerative Potential of Fatty Livers by Improving Lipid Metabolism and Increasing Autophagy

This is the authors' abstract. We don't add key points for this paper.

Introduction: Scarcity of adequate liver grafts results in significant lethality of liver transplant waitlist patients. Novel therapies to improve success of marginal grafts, namely livers with non-alcoholic fatty liver disease (NAFLD) may remedy this problem. NAFLD is the leading cause of discarded liver grafts given their poor regenerative ability and high failure rate. We propose liver-directed A20 gene therapy as a transformative approach to rehabilitate these organs. Methods: We overexpressed the NF-κB inhibitory, hepatoprotective protein A20 in livers of db/db mice, a model of NAFLD, by i.v. injection of a recombinant adenovirus (rAd.A20). Mice injected with rAd.β-galactosidase served as controls. Five days later, we performed a 2/3 partial hepatectomy (PH), and monitored mice for survival, recovery of liver function, and molecular markers of liver regeneration (LR). All experiments were approved by the IACUC. Results: Liver-directed expression of A20 significantly rescued (90% survival) db/db mice from lethality (50%) after PH. This related to improved hepatocyte proliferation (ki67 staining), and corresponded with a) decreased hepatic levels of cycle inhibitor, p21, b) reduced liver macrosteatosis/ improved lipid bioenergetics, c) increased autophagy, and d) lower inflammation. Notably, human fatty livers exhibit a similar “failure to regenerate” signature, i.e. increased p21, abnormal lipid metabolism, defective autophagy, and heightened NF-κB activation. We predict, as in db/db mice, A20 will correct these culprits. Conclusion: By correcting the molecular and metabolic pathogenic effectors that underscore failure of fatty livers to regenerate, liver-directed A20 based therapies are highly promising to rehabilitate these organs for transplantation.