Abstract
Objectives Our previous study showed that aldose reductase (AR) played key roles in fatty liver ischemia-reperfusion (IR) injury by regulating inflammatory response and energy metabolism. Here, we aim to investigate the role and mechanism of AR in the regeneration of normal and fatty livers after liver surgery. Methods The association of AR expression with liver regeneration was studied in the rat small-for-size liver transplantation model and the mice major hepatectomy and hepatic IR injury model with or without fatty change. The direct role and mechanism of AR in liver regeneration was explored in the AR knockout mouse model. Results Delayed regeneration was detected in fatty liver after liver surgery in both rat and mouse models. Furthermore, the expression of AR was increased in liver after liver surgery, especially in fatty liver. In a functional study, the knockout of AR promoted liver regeneration at day 2 after major hepatectomy and IR injury. Compared to wild-type groups, the expressions of cyclins were increased in normal and fatty livers of AR knockout mice. AR inhibition increased the expressions of PPAR-α and PPAR-γ in both normal liver and fatty liver groups after major hepatectomy and IR injury. In addition, the knockout of AR promoted the expressions of SDHB, AMPK, SIRT1, and PGC1-α and PPAR-Conclusions The knockout of AR promoted the regeneration of normal and fatty livers through regulating energy metabolism. AR may be a new potential therapeutic target to accelerate liver regeneration after surgery.
Highlights
Hepatectomy and liver transplantation are effective treatments for all kinds of liver diseases
The immunohistochemical staining (IHC)-staining data showed that hepatocyte regeneration with PCNA staining was markedly reduced in the small-for-size fatty graft compared with the small-for-size-normal graft at days 2, 4, 7, and 14 after transplantation (Figure 1(a))
Our results confirmed that fatty liver regeneration was delayed in the rat transplantation model and the mouse major hepatectomy and partial IR injury model
Summary
Hepatectomy and liver transplantation are effective treatments for all kinds of liver diseases. It is reported that more than 20% of the patients planned for liver resection have some degree of steatosis, which is associated with increased risk of postoperative complications and death [2, 3]. Steatotic liver graft increased the risk of primary nonfunction or dysfunction after transplantation compared to normal graft [2, 3]. Research showed that fatty liver is more vulnerable to ischemia-reperfusion (IR) injury and impaired liver regeneration and recovery, resulting in an amplified postoperative morbidity and mortality of patients [4, 5]. Clarifying the mechanism of fatty liver regeneration after an operation and finding effective intervention methods to promote fatty liver regeneration are very important for the recovery of liver function and improvement of long-term survival
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