Acid Ceramidase Protects Against Hepatic Ischemia/Reperfusion Injury by Modulating Sphingolipid Metabolism and Reducing Inflammation and Oxidative Stress

Abstract

Ceramide is a bioactive signaling lipid involved in the pathogenesis of numerous diseases. It also plays an important role in ischemia reperfusion (IR) injury via activation of inflammatory/oxidative stress-stimulated signaling pathways, resulting in tissue damage. Acid ceramidase is a lipid hydrolase that modulates the levels of ceramide, and as such has a potential therapeutic role in many human diseases where ceramide has been implicated. Here we investigated the therapeutic potential of recombinant acid ceramidase in a murine model of hepatic IR injury. Serum ALT, AST, and LDH activities, as well as oxidative stress (MDA) and inflammatory (MCP-1) markers, were increased in mice subjected to IR compared to a sham group. In contrast, these elevations were significantly lower in an IR group pretreated with a single injection of acid ceramidase. Histological examination by two different assessment criteria also revealed that acid ceramidase pretreatment alleviated IR-induced hepatocyte damage, including reduced evidence of cell death and necrosis. In addition, elevated ceramide and sphingosine levels were observed in the IR group compared to sham, and were markedly reduced when pretreated with acid ceramidase. In contrast, the levels of the protective signaling lipid, sphingosine-1-phosphate (S1P), were reduced following IR and elevated in response to acid ceramidase pretreatment. These changes in sphingolipid levels could be correlated with changes in the activities of several sphingolipid-metabolizing enzymes. Overall, these results indicated that sphingolipid changes were an important pathologic component of hepatic IR injury, and that acid ceramidase administration ameliorated these lipid changes and other downstream pathologic changes.

Paeonol Attenuates Hepatic Ischemia/Reperfusion Injury by Modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB Signaling Pathways

“…Oxidative stress, which results from ROS generation along with depletion of antioxidant defense mechanisms, plays a key role in the pathogenesis of HIR injury [ 5 , 55 , 56 ]. Excess oxygen radicals are produced during the reperfusion of the ischemic hepatocytes, causing lipid peroxidation of cellular membranes, inflammatory cell infiltration, neutrophil stimulation, and hepatic cell damage [ 57 , 58 ].…”

Asiatic acid ameliorates rifampicin‐ and isoniazid‐induced liver injury in vivo by regulating sphingolipid metabolism and mitogen‐activated protein kinase signalling pathways

“…Moreover, sphingolipids and their metabolites are a class of very important active molecules that are involved in many important signal transduction processes, such as the regulation of inflammation, oxidative stress, cell growth and programmed cell death. 32,33 Degs1 is a key gene encoding enzyme in the sphingolipid metabolism pathway that can regulate sphingolipid homeostasis. 34 Inhibition of Degs1 expression is hypothesized to benefit hepatic steatosis, which may provide a means of treating hepatic steatosis and metabolic disorders.…”

“…Sphingolipids are important components of the biofilm structure. Moreover, sphingolipids and their metabolites are a class of very important active molecules that are involved in many important signal transduction processes, such as the regulation of inflammation, oxidative stress, cell growth and programmed cell death 32,33 . Degs1 is a key gene encoding enzyme in the sphingolipid metabolism pathway that can regulate sphingolipid homeostasis 34 .…”

Acid ceramidase targeting pyruvate kinase affected trypsinogen activation in acute pancreatitis

“…Currently, exogenous ASAH1 was found to reduce inflammation in hepatic ischemia/reperfusion injury, which was presumably associated with the production of sphingosine-1-phosphate caused by sphingosine kinase activity upregulation (Jiang et al 2021 ). In our research, ASAH1 promoted inflammation, which may be related to sphingosine-1-phosphate hydrolase activation.…”