Oleylethanolamide is an endogenous PPAR-α agonist of the N-acylethanolamine class. Oleylethanolamide acts on GPR119 and TRPV1 to regulate fatty acid oxidation, reduce food intake and body weight, improve lipid profile and insulin sensitivity, inhibit the NF-κB pathway to decrease TNF-α, IL-6, COX-2, iNOS and ROS, and stimulate GLP-1 secretion. Oleylethanolamide can be used in studies on obesity, non-alcoholic fatty liver disease, type 2 diabetes and dyslipidemia[1-4].
In vitro, rat adipocytes were pre-incubated with 1μM Oleylethanolamide for 10min and then stimulated with insulin. Oleylethanolamide inhibited insulin-stimulated glucose uptake[5]. HUVECs were pretreated with 100μM Oleylethanolamide for 8h and then treated with 100μM H2O2 for 24h. Oleylethanolamide decreased intracellular ROS level, reduced 4-HNE production, increased SOD, CAT and GSH-Px antioxidant enzyme activities, and inhibited caspase-3 activation[6]. HUVECs were treated with 10-100μM Oleylethanolamide and 50μg/ml ox-LDL together for 24h. Oleylethanolamide inhibited ox-LDL-induced HUVEC proliferation and blocked ox-LDL-induced apoptosis. RAW264.7 cells were treated with 50μM Oleylethanolamide. Oleylethanolamide upregulated PPAR-α mRNA and downregulated iNOS and COX-2 mRNA. RAW264.7 cells stimulated with LPS and LDL were treated with 25-100μM Oleylethanolamide. Oleylethanolamide inhibited LPS-induced LDL oxidation, restored PPAR-α, and downregulated iNOS and COX-2[7].
In vivo, myocardial-injured Sprague-Dawley rats were intraperitoneally injected with 5mg/kg Oleylethanolamide twice daily for 3 days. Oleylethanolamide reduced left ventricular dilation, improved systolic and diastolic function, decreased cardiomyocyte apoptosis, and increased survival rate[8]. High-fat diet-fed C57BL/6J mice were intraperitoneally injected with 2.5mg/kg Oleylethanolamide daily for 8 weeks. Oleylethanolamide decreased body weight gain, energy intake and fat mass, improved fasting blood glucose and glucose tolerance, reduced heart weight, serum cholesterol and CK-MB, increased cardiac phosphorylation of AMPK, AKT and AS160, and modulated cardiac sphingomyelins and other lipids[9]. Wistar-Han rats were intraperitoneally injected with 10mg/kg Oleylethanolamide once daily for 2 weeks. Oleylethanolamide decreased liver triglyceride content, downregulated protein expression of ACC, FAS, DGAT1, DGAT2, SCD1, CD36, PPAR-γ and SREBP-1, and reduced ACC, FAS and DGAT activities[10].
References:[1] Fu J, Gaetani S, Oveisi F, et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature. 2003 Sep 4;425(6953):90-3.
[2] Matias I, Gonthier M-P, Petrosino S, et al. Role and regulation of acylethanolamides in energy balance: focus on adipocytes and β-cells. Br J Pharmacol. 2007;152(5):676-90.
[3] Pandey P, Chaurasiya N D, Tekwani B L, et al. Interactions of endocannabinoid virodhamine and related analogs with human monoamine oxidase-A and-B. Biochem Pharmacol. 2018 Sep;155:82-91
[4] Guzman M, Lo Verme J, Fu J, et al. Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem. 2004 Jul 2;279(27):27849-54.
[5] Gonzalez-Yanes C, Serrano A, Bermúdez-Silva F J, et al. Oleylethanolamide impairs glucose tolerance and inhibits insulin-stimulated glucose uptake in rat adipocytes through p38 and JNK MAPK pathways. Am J Physiol Endocrinol Metab. 2005 Nov;289(5):E923-9.
[6] Shen X, Zhang Y, Xu Z, et al. KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response. Cell Death Dis. 2022;13:303.
[7] Fan A, Wu X, Wu H, et al. Atheroprotective Effect of Oleoylethanolamide(OEA) Targeting Oxidized LDL. PLoS ONE. 2014 Jan;9(1):e85337.
[8] Su H, Samsamshariat A, Fu J, et al. Oleylethanolamide activates Ras-Erk pathway and improves myocardial function in doxorubicin-induced heart failure. Endocrinology. 2006 Feb;147(2):827-34.
[9] Comella F, Aragón-Herrera A, Pirozzi C, et al. Oleoylethanolamide mitigates cardiometabolic disruption secondary to obesity induced by high-fat diet in mice. Life Sci. 2024;359:123226.
[10] Romano A, Friuli M, Del Coco L, et al. Chronic Oleoylethanolamide Treatment Decreases Hepatic Triacylglycerol Level in Rat Liver by a PPARy/SREBP-Mediated Suppression of Fatty Acid and Triacylglycerol Synthesis. Nutrients. 2021 Feb;13(2):394.