Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
Curr Med Chem. 2021;28(1):169-180. doi: 10.2174/0929867327666200303122734.
Dysfunction of the endocannabinoid system (ES) has been identified in nonalcoholic fatty liver disease (NAFLD) and associated metabolic disorders. Cannabinoid receptor type 1 (CB1) expression is largely dependent on nutritional status. Thus, individuals suffering from NAFLD and metabolic syndrome (MS) have a significant increase in ES activity. Furthermore, oxidative/ nitrosative stress and inflammatory process modulation in the liver are highly influenced by the ES. Numerous experimental studies indicate that oxidative and nitrosative stress in the liver is associated with steatosis and portal inflammation during NAFLD. On the other hand, inflammation itself may also contribute to reactive oxygen species (ROS) production due to Kupffer cell activation and increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The pathways by which endocannabinoids and their lipid-related mediators modulate oxidative stress and lipid peroxidation represent a significant area of research that could yield novel pharmaceutical strategies for the treatment of NAFLD. Cumulative evidence suggested that the ES, particularly CB1 receptors, may also play a role in inflammation and disease progression toward steatohepatitis. Pharmacological inactivation of CB1 receptors in NAFLD exerts multiple beneficial effects, particularly due to the attenuation of hepatic oxidative/nitrosative stress parameters and significant reduction of proinflammatory cytokine production. However, further investigations regarding precise mechanisms by which CB1 blockade influences the reduction of hepatic oxidative/nitrosative stress and inflammation are required before moving toward the clinical phase of the investigation.
内源性大麻素系统 (ES) 的功能障碍已在非酒精性脂肪性肝病 (NAFLD) 和相关代谢紊乱中得到证实。大麻素受体 1 (CB1) 的表达在很大程度上取决于营养状况。因此，患有 NAFLD 和代谢综合征 (MS) 的个体的 ES 活性显著增加。此外，肝脏中的氧化/硝化应激和炎症过程调节受 ES 的高度影响。大量的实验研究表明，肝脏中的氧化和硝化应激与 NAFLD 期间的脂肪变性和门脉炎症有关。另一方面，炎症本身也可能由于枯否细胞激活和增加的烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶活性而导致活性氧 (ROS) 的产生。内源性大麻素及其脂质相关介质调节氧化应激和脂质过氧化的途径是一个重要的研究领域，可能为 NAFLD 的治疗提供新的药物策略。累积的证据表明，ES，特别是 CB1 受体，也可能在炎症和向脂肪性肝炎的疾病进展中发挥作用。在 NAFLD 中，CB1 受体的药理学失活具有多种有益作用，特别是由于肝氧化/硝化应激参数的减弱和促炎细胞因子产生的显著减少。然而，在向研究的临床阶段推进之前，需要进一步研究 CB1 阻断如何影响肝氧化/硝化应激和炎症的减少的确切机制。
