n-oleoylethanolamine and Liver-Cirrhosis

Nonalcoholic fatty liver disease (NAFLD) is one of the most common noncommunicable diseases worldwide. The present study aimed to investigate the effects of oleoylethanolamide (OEA) supplementation combined with calorie restriction on inflammation, body composition, and hepatic fibrosis among obese patients with NAFLD. In this 12-week randomized clinical trial, 76 obese patients newly diagnosed with NAFLD were randomly allocated into either OEA or placebo group. The weight-loss diet was also designed for both groups. Pre- and postintervention messenger RNA expression levels of the transcription factor nuclear factor-κB (NF-κB), interleukin-6 (IL-6) and IL-10, body composition, and NAFLD fibrosis score were assessed. At the end of the study, the OEA group showed lower NF-κB and IL-6 expression levels compared to the placebo (p < .01). However, IL-10 expression level was approximately twofold higher in the OEA group compared to the placebo group (p = .008). A significant reduction was observed in the fat mass of the OEA group compared to the placebo (p = .044) postintervention. In addition, OEA supplementation led to a significant increase in fat-free mass in the OEA group compared to the placebo (p = .032). A remarkable increase was observed in resting metabolic rate (RMR) in the OEA group (p = .009); however, it was not found in the placebo group. There were no significant between-group differences in RMR postintervention. In addition, no significant within-and between-group differences were observed in the NAFLD fibrosis score at the end of the trial. Treatment with OEA along with weight-loss intervention could significantly improve inflammation and body composition in patients with NAFLD.

Topics: Adult; Body Composition; Caloric Restriction; Dietary Supplements; Endocannabinoids; Female; Humans; Interleukin-10; Interleukin-6; Liver Cirrhosis; Male; NF-kappa B; Non-alcoholic Fatty Liver Disease; Obesity; Oleic Acids; Weight Loss

Oleoylethanolamide (OEA), an endocannabinoid-like molecule, was revealed to modulate lipid metabolism through a peroxisome proliferator-activated receptor-α (PPAR-α) mediated mechanism. In present study, we further investigated the activities and mechanisms of OEA in ameliorating hepatic fibrosis in Sv/129 mice induced by a methionine choline-deficient (MCD) diet or thioacetamide (TAA) treatment. Liver fibrosis development was assessed by Hematoxylin-eosin and Sirius red staining. Treatment with OEA (5 mg/kg/day, intraperitoneal injection, i.p.) significantly attenuated the progress of liver fibrosis in both two experimental animal models by blocking the activation of hepatic stellate cells (HSCs). Gene expression analysis of hepatic tissues indicated that OEA inhibited the expression of α-smooth muscle action (α-SMA) and collagen matrix, fibrosis markers, and genes involved in inflammation and extracellular matrix remodeling. In vitro studies showed that OEA inhibited transforming growth factor β1-stimulated HSCs activation through suppressing Smad2/3 phosphorylation, α-SMA expression and myofibroblast transformation. These improvements could not be observed in PPAR-α knockout mice models with OEA administration, which suggested all the anti-fibrotic effects of OEA in vivo and in vitro were mediated by PPAR-α activation. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating hepatic fibrosis development through the inhibition of HSCs activation in liver and therefore may be a potential therapeutic agent for liver fibrosis.

Topics: Animals; Blotting, Western; Disease Models, Animal; Endocannabinoids; Fluorescent Antibody Technique; Hepatic Stellate Cells; Ligands; Liver Cirrhosis; Mice; Mice, 129 Strain; Mice, Knockout; Oleic Acids; PPAR alpha; Real-Time Polymerase Chain Reaction

Endocannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid-related molecules like oleoyl-ethanolamine (OEA) and palmitoyl-ethanolamine (PEA) have also been identified. AEA contributes to the pathogenesis of cardiovascular alterations in experimental cirrhosis, but data on the endocannabinoid system in human cirrhosis are lacking. Thus, we aimed to assess whether circulating and hepatic endocannabinoids are upregulated in cirrhotic patients and whether their levels correlate with systemic haemodynamics and liver function.. The endocannabinoid levels were measured in peripheral and hepatic veins and liver tissue by isotope-dilution liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. Systemic haemodynamics were assessed by the transthoracic electrical bioimpedance technique. Portal pressure was evaluated by hepatic venous pressure gradient.. Circulating AEA and, to a greater extent, PEA and OEA were significantly higher in cirrhotic patients than in controls. PEA and OEA were also increased in the cirrhotic liver tissue. AEA, OEA and PEA levels were significantly higher in peripheral than in the hepatic veins of cirrhotic patients, while the opposite occurred for 2-AG. Finally, circulating AEA, OEA and PEA correlated with parameters of liver function, such as serum bilirubin and international normalized ratio. No correlations were found with systemic haemodynamics.. The endocannabinoid system is upregulated in human cirrhosis. Peripheral AEA is increased in patients with a high model of end-stage liver disease score and may reflect the extent of liver dysfunction. In contrast, the 2-AG levels, the other major endocannabinoid, are not affected by cirrhosis. The upregulation of the endocannabinoid-related molecules, OEA and PEA, is even greater than that of AEA, prompting pharmacological studies on these compounds.

Topics: Adult; Amides; Arachidonic Acids; Bilirubin; Biomarkers; Cannabinoid Receptor Modulators; Case-Control Studies; Chromatography, Liquid; Electric Impedance; Endocannabinoids; Ethanolamines; Female; Glycerides; Hemodynamics; Humans; International Normalized Ratio; Italy; Liver; Liver Cirrhosis; Liver Function Tests; Male; Mass Spectrometry; Middle Aged; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Radioisotope Dilution Technique; Severity of Illness Index; Up-Regulation

Topics: Amides; Arachidonic Acids; Biomarkers; Cannabinoid Receptor Modulators; Endocannabinoids; Ethanolamines; Glycerides; Hemodynamics; Humans; International Normalized Ratio; Liver; Liver Cirrhosis; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Severity of Illness Index; Up-Regulation