Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes

Tutunchi, Helda; Ostadrahimi, Alireza; Saghafi-Asl, Maryam; Hosseinzadeh‐Attar, Mohammad Javad; Shakeri, Ahmad; Asghari‐Jafarabadi, Mohammad; Farrin, Nazila; Naemi, Mohammad; Hasankhani, Milad

doi:10.1016/j.phrs.2020.104770

Cited by 44 publications

(41 citation statements)

References 46 publications

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“…In the context of the current work, the hepatic upregulation in the AEA levels is less important, since its expected lipogenic activity is most likely negated in the presence of AM6545 or in mice lacking the CB 1 R in hepatocytes. However, amelioration of hepatic steatosis by blocking the CB 1 R can be mediated via upregulating the levels of OEA and PEA, whose antisteatotic effect was previously reported [ 38 , [66] , [67] , [68] ]. Specifically, both are known to regulate the expression of PPARα target genes implicated in FFA mobilization and oxidation and affect mitochondrial flexibility in hepatocytes [ 66 , 69 ].…”

Section: Discussionmentioning

confidence: 94%

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

Azar

Udi

Drori

et al. 2020

Molecular Metabolism

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Objective The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB 1 R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. Methods We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB 1 R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. Results Using an unbiased normalized phylogenetic profiling analysis, we found that the CB 1 R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPARα), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB 1 R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPARα −/− mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPARα as well as elevated hepatic levels of the PPARα-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPARα. Both of these signaling molecules were modulated by the CB 1 R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB 1 R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB 1 R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPARα. Conclusions We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPARα signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB 1 R blockade.

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Section: Discussionmentioning

confidence: 94%

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

Azar

Udi

Drori

et al. 2020

Molecular Metabolism

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“…Previous studies have demonstrated that TC/HDL-C, LDL-C/HDL-C, and TG/ HDL-C ratios are better indicators of CVD, which is one of the most major causes of morbidity and mortality in patients with NAFLD. [36][37][38][39][40] The mechanism by which OEA exerts beneficial metabolic effects is mainly attributed to PPAR-α. 21,26 Activation of PPAR-α by OEA and the consequential transcription of PPAR-α modulated genes lead to a cascade of events that finally affects metabolic parameters.…”

Section: Discussionmentioning

confidence: 99%

Effects of oleoylethanolamide supplementation on atherogenic indices and hematological parameters in patients with nonalcoholic fatty liver disease: A clinical trial

Tutunchi

Naeini

Saghafi-Asl

et al. 2020

Health Promot Perspect

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Background: Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease in the world. The current interventional trial aimed to evaluate the effects of supplementation with oleoylethanolamide (OEA) in combination with weight loss intervention on some atherogenic indices as well as hematological parameters in patients newly diagnosed with NAFLD. Methods: In this triple-blinded, randomized, placebo-controlled clinical trial, 76 obese patients with NAFLD confirmed by ultra-sonographic findings were randomly assigned to receive a weight reduction diet plus either 250 mg OEA (n=38) or placebo (n=38) for 12 weeks. Atherogenic factors including total cholesterol/high-density lipoprotein cholesterol (HDL-C),low-density lipoprotein cholesterol (LDL-C)/HDL-C, triglyceride (TG)/HDL-C, non-HDL-C/HDL-C ratios and non-HDL-C level, as well as hematological parameters were assessed before and after intervention. Results: After adjustment for potential confounding factors, between group analyses demonstrated a significantly lower LDL-C/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C ratios in the OEA group compared to the placebo, post-intervention (95% confidence interval [CI]:0.06 to 0.85, P = 0.024; 95% CI: -2.06 to -0.05, P = 0.039; 95% CI: -1.05 to -0.02, P = 0.042,respectively). Additionally, OEA supplementation could significantly decrease the levels of red blood cell distribution width (RDW) compared to the placebo at the endpoint after considering potential confounding variables (95% CI: -0.56 to -0.003, P = 0.041). No significant differences were found between the two study groups in terms of other hematological parameters. Conclusion: The results of the current study indicated that OEA supplementation had beneficial effects on LDL-C/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C ratios as well as RDW in obese patients with NAFLD. Trial Registration: IRCT20110530006652N2; https://www.irct.ir/trial/37228.

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“…In previous clinical trials, doses of 250 mg/d of OEA oral intake by participants exhibited satisfactory safety when compared to placebo. Also, even when OEA was given to humans at a dose of 250 mg/d for 3 months, no side effects were reported (28,32).…”

Section: Oea and Safetymentioning

confidence: 98%

Oleoylethanolamide, A Bioactive Lipid Amide, as A Promising Treatment Strategy for Coronavirus/COVID-19

Ghaffari

Roshanravan

Ostadrahimi

et al. 2020

Archives of Medical Research

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E20_423 2 (WHO) as a global pandemic. With the emergence of the COVID-19 virus and considering the lack of effective pharmaceutical treatment for it, there is an urgent need to identify safe and effective drugs or potential adjuvant therapy in this regard. Bioactive lipids with an array of known healthpromoting properties can be suggested as effective agents in alleviating acute respiratory stress induced by virus. The bioactive lipid amide, oleoylethanolamide (OEA), due to several distinctive homeostatic properties, including anti-inflammatory activities, modulation of immune response, and anti-oxidant effects can be considered as a novel potential pharmacological alternative for the management of COVID-19.

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Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: Effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes

Cited by 44 publications

References 46 publications

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

Effects of oleoylethanolamide supplementation on atherogenic indices and hematological parameters in patients with nonalcoholic fatty liver disease: A clinical trial

Oleoylethanolamide, A Bioactive Lipid Amide, as A Promising Treatment Strategy for Coronavirus/COVID-19

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