<b>The Effect of Oleoylethanolamide Supplementation on Pyroptotic Cell Death in Obese Patients with Non-Alcoholic Fatty Liver Disease: A Double-Blind Randomized Controlled Clinical Trial</b>

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver diseases globally. Recent interest has been aroused in the role of pyroptosis, a form of cell death, that contributes to hepatocyte destruction in liver damage. This study aimed to investigate the effects of OEA supplementation on the pyroptosis pathway in NAFLD patients. Methods: The current study was a double-blind, randomized controlled clinical trial conducted in 65 adults with obesity and newly-diagnosed NAFLD. For 12 weeks, participants received personalized calorie-restricted diets plus either two daily 125-mg oleoylethanolamide (OEA) capsules or matching placebo capsules. The main objective was to assess the impact of OEA on serum levels of lipopolysaccharide-binding protein (LBP) and expression levels of key genes in the pyroptosis pathway. Results: The intervention impacted the expression levels of Toll-like receptor 4 (TLR4), Myeloid differentiation primary response 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3), Cysteine-dependent aspartate-specific protease (Caspase) 1, Caspase 8, Interleukin (IL)-1β, and IL-18 in PBMCs, presented as log fold changes with median values and 95% confidence intervals. TLR4 and Caspase 8 expression levels increased, while it was decreased for the rest. However, none of the changes between groups were statistically significant (TLR4, p=0.48; MyD88, p=0.47; TRIF, p=0.06; NLRP3, p=0.70; Caspase 1, p=0.81; Caspase 8, p=0.15; IL-1β, p=0.98; IL-18, p=0.65). Serum LBP levels also showed no significant differences between groups (p=0.16) or within groups. Conclusion: OEA supplementation could not make any significant difference in the pyroptotic pathway in obese adults with NAFLD. Further studies are warranted to corroborate these findings.