Abstract
Acute liver injury is a rapidly deteriorating clinical condition with markedly high morbidity and mortality. Oleoylethanolamide (OEA) is an endogenous lipid messenger with multiple bioactivities, and has therapeutic effects on various liver diseases. However, effects of OEA on acute liver injury remains unknown. In this study, effects and mechanisms of OEA in lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury in mice were investigated. We found that OEA treatment significantly attenuated LPS/D-Gal-induced hepatocytes damage, reduced liver index (liver weight/body weight), decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Moreover, mechanism study suggested that OEA pretreatment significantly reduced hepatic MDA levels, increased Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) activities via up-regulate Nrf-2 and HO-1 expression to exert anti-oxidation activity. Additionally, OEA markedly reduced the expression levels of Bax, Bcl-2 and cleaved caspase-3 to suppress hepatocyte apoptosis. Meanwhile, OEA remarkedly reduced the number of activated intrahepatic macrophages, and alleviated the mRNA expression of pro-inflammatory factors, including TNF-α, IL-6, MCP1 and RANTES. Furthermore, OEA obviously reduced the expression of IL-1β in liver and plasma through inhibit protein levels of NLRP3 and caspase-1, which indicated that OEA could suppress NLRP3 inflammasome pathway. We further determined the protein expression of PPAR-α in liver and found that OEA significantly increase hepatic PPAR-α expression. In addition, HO-1 inhibitor ZnPP blocked the therapeutic effects of OEA on LPS/D-Gal-induced liver damage and oxidative stress, suggesting crucial role of Nrf-2/HO-1 pathway in the protective effects of OEA in acute liver injury. Together, these findings demonstrated that OEA protect against the LPS/D-Gal-induced acute liver injury in mice through the inhibition of apoptosis, oxidative stress and inflammation, and its mechanisms might be associated with the Nrf-2/HO-1 and NLRP3 inflammasome signaling pathways.
Highlights
Acute liver injury, named acute liver failure, is a dramatic clinical syndrome associated with severe liver dysfunction and high mortality rates generally resulting from sepsis, viral hepatitis, autoimmune hepatitis, alcohol abuse or drugs overdose (Bernal and Wendon, 2013; Stravitz and Lee, 2019)
To detect the protective role of OEA against acute liver injury induced by LPS/D-Gal injection, we examined histopathological changes, liver weight, body weight and calculated the liver index, the plasma Alanine transaminase (ALT), Aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels were analyzed
OEA dramatically reactivated the expression of Nuclear factor-E2-related factor 2 (Nrf-2), HO-1 and GCLC in the liver (Figures 3D–G). These results suggested that OEA could attenuate hepatic oxidative stress through Nrf-2/HO-1 pathway in LPS/D-Gal-induced acute liver injury
Summary
Named acute liver failure, is a dramatic clinical syndrome associated with severe liver dysfunction and high mortality rates generally resulting from sepsis, viral hepatitis, autoimmune hepatitis, alcohol abuse or drugs overdose (Bernal and Wendon, 2013; Stravitz and Lee, 2019). Lipopolysaccharide (LPS), an endotoxin component of Gramnegative bacterial cell wall, can induce acute liver injury in mice together with D-Galactosamine (D-Gal). This widely used animal model could accurately mimic all the complications of the fulminant liver failure in human, including hepatocyte apoptosis, intracellular oxidative stress and inflammation (Lei et al, 2020; Yang et al, 2020). Previous studies have reported that the redoxresponsive transcription factor Nuclear factor-E2-related factor 2 (Nrf-2) and the anti-oxidant enzyme Heme Oxygenase-1(HO-1) play a crucial role in the regulation of oxidative stress during the pathogenesis of liver injury (Ge et al, 2017; Saeedi et al, 2020). The elevated levels of SOD and GSH-px generally reflect enhanced abilities against oxidative stress
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