Oleic Acid Protects against Hepatic Ischemia and Reperfusion Injury in Mice by Inhibiting AKT/mTOR Pathways

Abstract

Hepatic ischemia-reperfusion (I/R) injury is a serious complication in patients who have undergone hepatic surgery such as orthotopic liver transplantation and partial hepatectomy. Recently, a new cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), was reported to protect against hepatic I/R injury. However, the protective mechanism of UDCA-LPE is not fully understood. Therefore, we conducted this study to explore its underlying mechanism. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze the liver lipid metabolism changes in mice during I/R. KEGG enrichment indicated that UDCA-LPE is likely to exert its protective role by regulating fatty acid (FA) metabolism. Further analysis found that UDCA-LPE significantly increased the ratio of oleic acid (OA) to palmitic acid (PA). We found that mice pretreated with OA improved tolerance to hepatic I/R injury. In addition, the phosphorylation level of AKT was markedly upregulated during oxidative stress to promote p65 nuclear translocation, triggering an inflammatory response that exacerbated cell damage and OA treatment significantly inhibited this process. Notably, OA was found to inhibit H2O2-induced oxidative stress, inflammation, and cell death in HepG2 cells. Furthermore, we found that OA supplementation to the medium did not result in a significant increase in intracellular OA, but marked increase in the ratio of OA to PA, which may be an important mechanism for the inflammatory response induced by oxidative stress during I/R. Finally, we demonstrated that OA increased the level of autophagy in HepG2 cells, which may be one of the protective mechanisms against oxidative stress. Collectively, this study revealed that FA metabolism functionally determines the oxidative stress-related inflammation caused by hepatic I/R. We hypothesize that OA treatment may be a promising strategy for preventing and treating I/R-induced liver damage.

The Role of Mitochondria in Liver Ischemia‐Reperfusion Injury: From Aspects of Mitochondrial Oxidative Stress, Mitochondrial Fission, Mitochondrial Membrane Permeable Transport Pore Formation, Mitophagy, and Mitochondria‐Related Protective Measures

“…To determine the effect of PPARγ, some researchers used PPARγ agonist rosiglitazone and connecting peptide to treat mice, which decreased the occurrence of IRI [69]. PPARγ has a protective effect on IRI, which increases the level of SOD and H 2 O 2 hydrolase, decreases the level of nicotinamide adenine dinucleotide phosphate oxidase, slows down the degradation of Bcl-2 and Bcl-xl, and significantly reduces the phosphorylation level of AKT to inhibit p65 nuclear translocation and inflammatory response [70][71][72]. Besides, peroxisome proliferatoractivated receptor γ coactivator 1α (PGC-1α) is a major regulator of mitochondria and ROS, which promotes the release of a series of antioxidant enzymes to resist oxidative injury [73].…”

Long-term cold storage preservation does not affect fatty livers from rats fed with a methionine and choline deficient diet

“…Moreover, oleic acid has been confirmed to be more steatogenic, though less apoptotigenic, than palmitic acid in hepatocytes cell cultures [ 43 ]. Recent findings have demonstrated that mice pretreated with oleic acid improved their tolerance to hepatic I/R injury [ 44 ]. The proposed mechanism is that oleic acid could be able to downregulate the AKT/mTOR phosphorylation pathway and the consequent p65 nuclear translocations needed to initiate the inflammatory response [ 44 ].…”

“…Recent findings have demonstrated that mice pretreated with oleic acid improved their tolerance to hepatic I/R injury [ 44 ]. The proposed mechanism is that oleic acid could be able to downregulate the AKT/mTOR phosphorylation pathway and the consequent p65 nuclear translocations needed to initiate the inflammatory response [ 44 ]. These findings help to justify the low susceptibility of MCD livers to prolonged cold preservation.…”

Regulation of autophagy protects against liver injury in liver surgery‐induced ischaemia/reperfusion

“…Pretreatment with oleic acid (OA) improved the tolerance of mice undergoing hepatic I/R injury by downregulating the phosphorylation of AKT and oxidative stress. An in vitro study showed that OA effectively inhibited oxidative stress, inflammation and cell death in hydrogen peroxide (H 2 O 2 )-treated HepG2 cells by upregulating autophagy 59. Other investigations showed that plant extract pretreatment attenuated hepatic I/R injury via inhibition of autophagy and apoptosis.…”