Oleoylethanolamide Protects Against Acute Liver Injury by Regulating Nrf-2/HO-1 and NLRP3 Pathways in Mice

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.

Oleoylethanolamide Reduces Hepatic Oxidative Stress and Endoplasmic Reticulum Stress in High-Fat Diet-Fed Rats

“…OEA has been demonstrated to exert a plethora of protective effects including anti-obesity, anti-inflammatory, and antioxidant properties thus supporting its potential use for the treatment of obesity and eating-related disorders [ 18 , 25 , 26 ]. In fact, as a drug, OEA reduces food intake and body weight gain [ 20 , 27 , 28 ] in both lean and obese rodents and reduces lipopolysaccharide-induced liver injury in mice [ 29 ]. Moreover, it has been demonstrated that OEA reduces lipid synthesis and lipoprotein secretion in hepatocytes [ 30 ] and improves HFD-induced liver steatosis in rats [ 31 ] and humans [ 32 , 33 ].…”

Decreased dysmenorrhea pain in girls by reducing oxidative stress and inflammatory biomarkers following supplementation with oleoylethanolamide: A randomized controlled trial

“…Similarly, a novel experiment conducted on a mice model of acute liver injury indicated that OEA treatment can significantly alleviate the lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced liver injury through reducing MDA levels, enhancing superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities through upregulation of Nrf-2 and HO-1 expression. 19 Conversely, in a randomized clinical trial, Payahoo et al examined the effect of 8-week OEA supplementation on oxidative stress in obese people, in which changes in MDA levels and total antioxidant status were undetectable. 13 The imbalance between ROS production and detoxification in the body which leads to oxidative stress is linked to the pathogenesis of more than 100 diseases as well as dysmenorrhea.…”

The Role of PPAR Alpha in the Modulation of Innate Immunity

“…In turn, the liver protein levels of IL-1β and NLRP3 inflammasome components, NLRP3 protein and pro-caspase-1, were enhanced after LPS/ d -Gal injection in mice. The increase in these proteins was alleviated by OEA addition to the diet [ 100 ]. The OEA anti-inflammatory effects were also evident in dextran sulfate sodium (DSS)-induced mice colitis, and the effect was mediated by the inhibition of NLRP3, NF-κB, or MyD88-dependent pathways [ 101 ].…”