Abstract
Hepatic ischemia and reperfusion injury are characterized by impaired autophagy, mitochondrial dysfunction, and subsequent compromise of cellular homeostasis following hepatic surgery or transplantation. Nobiletin, a natural flavonoid, is a beneficial antioxidant that possesses anti-inflammatory and anti-cancer activities. We investigated the effect of nobiletin on hepatic IR injury and described the underlying mechanisms. C57BL/6 mice were subjected to 60 min of partial hepatic ischemia, treated with nobiletin (5 mg/kg) or vehicle at the start of reperfusion, and killed at 5 h of reperfusion. Hepatic ischemia and reperfusion increased hepatocellular oxidative damage, inflammation, and cell death, but these changes were alleviated upon nobiletin treatment. Nobiletin increased the expression of proteins that control autophagy, mitochondrial dynamics, and biogenesis. Specifically, the SIRT-1/FOXO3a and PGC-1α pathways were activated by nobiletin. IR-induced AKT activation was associated with FOXO3a phosphorylation, which resulted in a significant reduction in the nuclear FOXO3a levels and potentially attenuated autophagy-regulatory gene expression. Nobiletin increased FOXO3a expression and its nuclear translocation via the inhibition of AKT. Specific inhibition of SIRT-1 abolished the protective effect of nobiletin, causing decreased FOXO3a expression, followed by autophagy induction and decreased PGC-1α expression and mitochondrial dynamics. Taken together, our data indicate that SIRT-1 directly mediates the protective effect of nobiletin against hepatic ischemia and reperfusion injury. The activation of autophagy and mitochondrial function through the SIRT-1/FOXO3a and PGC-1α pathways indicate that nobiletin could have therapeutic potential for treating hepatic ischemia and reperfusion injury.
Highlights
Hepatic ischemia and reperfusion (IR) injury, caused by blood deprivation followed by reperfusion, occurs in various clinical settings, including hepatic resection surgery, transplantation, and shock
Nobiletin attenuated hepatocellular damage induced by hepatic IR injury Liver damage was assessed by measuring plasma ALT and AST, which were significantly increased in the hepatic IR group compared with the sham group (Fig. 2a)
We found that protein expression of PGC-1α, mitofusin 2 (MFN-2), and optic atrophy 1 (OPA-1) was decreased, whereas dynamin-related protein 1 (DRP-1) expression was increased in the hepatic IR group, which was alleviated upon nobiletin treatment (Fig. 5b)
Summary
Hepatic ischemia and reperfusion (IR) injury, caused by blood deprivation followed by reperfusion, occurs in various clinical settings, including hepatic resection surgery, transplantation, and shock. The pathophysiology of hepatic IR injury contributes to an increased rate of acute liver failure, graft rejection, and chronic hepatic dysfunction[1,2]. IR injury affects parenchymal hepatocytes, nonparenchymal cells (liver sinusoidal endothelial, Kupffer, and hepatic stellate cells), and extrahepatic components (cytokines)[4]. Effective therapeutic strategies for treating or preventing this devastating syndrome are clinically limited, despite our advanced understanding of IR injury mechanisms. Autophagy is a highly conservative cellular process that degrades and recycles misfolded or dysfunctional proteins and damaged organelles to maintain cellular homeostasis[5]
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