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A Potential Shield Against IR Injury

Hepatic ischemia-reperfusion (IR) injury poses significant challenges in liver transplantation and other critical conditions. Effective strategies for mitigating this damage have remained limited, until now. Recent research has unveiled the crucial role of the insulin-induced gene 2 (Insig2) in safeguarding against hepatic IR injury. Discover how Insig2's protective effects, mediated through the pentose phosphate pathway (PPP), hold promising potential for innovative therapeutic interventions. Find out how manipulating Insig2-related pathways could revolutionize the prevention and treatment of liver IR damage, addressing the pressing need for effective solutions.

Hepatic ischemia-reperfusion (IR) injury is a critical concern in liver transplantation, liver resection, and hypovolemic shock. It can lead to severe liver damage, graft dysfunction, and rejection. Despite efforts to address this problem, effective strategies remain limited. Understanding the mechanisms underlying IR injury is crucial for developing treatments and overcoming the shortage of liver donors. Recent research has shed light on the role of the insulin-induced gene 2 (Insig2) in protecting against hepatic IR injury, offering new avenues for therapeutic intervention.

Insig2 and its Significance

Insig2 is an endoplasmic reticulum protein involved in regulating sterol regulatory element-binding protein (SREBP) activation and lipogenesis in the liver. Previous studies have suggested that Insig2 suppression is associated with insulin-induced lipogenesis, and its remaining counterpart, Insig1, may not sufficiently block SREBP activation. Insig2 also influences glucose and lipid metabolism as well as immune responses. Given the metabolic and immune disturbances observed in hepatic IR injury, investigating the regulatory role of Insig2 becomes crucial.

Research Findings

A recent study explored the impact of Insig2 on hepatic IR injury using both in vitro and in vivo models. Researchers found reduced Insig2 expression in primary liver cells exposed to hypoxia/reoxygenation insult and in livers subjected to IR surgery. To investigate the protective role of Insig2, they employed mice with global Insig2 knockout and hepatocyte-specific Insig2 overexpression. The results demonstrated that Insig2 acts as a safeguard against hepatic IR injury. Insig2 deficiency exacerbated liver damage, while Insig2 overexpression had a protective effect. Further investigation revealed that Insig2 interacts with the pentose phosphate pathway (PPP), and increasing PPP substrate levels effectively reduced hepatic IR damage.

Mechanisms Underlying Insig2 Protection

Insig2's protective effects are attributed to its involvement in the PPP, a metabolic pathway crucial for antioxidant defense. Insig2 overexpression activated the PPP, preserving redox homeostasis and mitigating oxidative stress during IR injury. In contrast, Insig2 deficiency impaired PPP activity and disrupted redox balance, exacerbating liver damage. These findings highlight the importance of the PPP in Insig2-mediated protection against hepatic IR injury.

Potential Therapeutic Strategies

Manipulating Insig2-related pathways, such as the PPP, could serve as potential therapeutic approaches for preventing and treating liver IR damage. The study demonstrated that inhibiting PPP activity with a specific inhibitor abolished the protective effects of Insig2 overexpression. Conversely, delivering glucose 6-phosphate (G6P), a PPP substrate, using an esterase-responsive nanoparticle (ERP) attenuated liver IR injury in mice. This approach shows promise in protecting the liver against IR damage.

Histological observations showed less hepatocellular apoptosis, necrosis and recruitment of inflammation cells induced by G6P nanoparticles preconditioning when compared to control mice.
Yichao Wu, Changbiao Li, Abid Ali Khan et al. Insulin-induced Gene 2 Protects against Hepatic Ischemia-reperfusion Injury via Metabolic Remodeling, 06 June 2023, PREPRINT (Version 1) available at Research Square [ ]

Potential of targeting Insig2-related pathways

Hepatic IR injury poses significant challenges in liver transplantation and other clinical scenarios. Recent research has shed light on the protective role of Insig2 in hepatic IR injury by regulating the PPP and maintaining redox homeostasis. Manipulating Insig2 or delivering PPP substrates like G6P may hold promise as therapeutic strategies for mitigating liver damage caused by IR injury. Further research is needed to explore the full potential of targeting Insig2-related pathways and develop effective treatments for hepatic IR injury, ultimately improving patient outcomes and addressing the shortage of liver donors.

In summary, our investigation revealed that hepatocyte Insig2 is a protective factor against liver IR injury by optimizing glucose metabolism via the PPP, thus strengthening the antioxidant defenses and enhancing redox homeostasis of hepatocytes. Furthermore, we concluded that increasing the G6P levels may function as a novel treatment approach for liver donor preservation.