Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver

Abstract

Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ) protects the liver against IRI, but with unidentified direct target gene(s) and unclear mechanism(s). Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI.

Keywords: FAM3A; LncRNA; PPARγ; liver ischemia-reperfusion injury; miRNA.

Figure 1

FAM3A inhibited NF-κB activation induced by oxidative stress in HepG2 cells. Oxidative stress increased nuclear localization of NF-κB, which was reversed by FAM3A overexpression. Moreover, FAM3A-induced inhibition of NF-κB was partially reversed by P2 receptor antagonist suramin. The scale bar indicated in the images is 25μm.

Figure 2

Proposed protective mechanisms of PPARγ-FAM3A axis in liver IRI. FAM3A exerts beneficial effects on liver IRI via the activation of ATP-PI3K-Akt pathways, inhibition of inflammation, and attenuation of oxidative stress. As a direct target gene of PPARγ, FAM3A mediates the protective effects of PPARγ activation on liver IRI. IRI, ischemia/reperfusion injury. MDA, methane dicarboxylic aldehyde; MPO, myeloperoxidase.