Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11459, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11459, Saudi Arabia; Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Egypt.
Biochem Pharmacol. 2019 Jun;164:252-262. doi: 10.1016/j.bcp.2019.04.018. Epub 2019 Apr 18.
Renin-angiotensin-aldosterone system (RAS) has been implicated in non-alcoholic fatty liver disease (NAFLD); the most common cause of chronic liver diseases. There is accumulating evidence that altered TLR4 and Sphingosine kinase 1(SphK1)/sphingosine1phosphate (S1P) signaling pathways are key players in the pathogenesis of NAFLD. Cross talk of the sphingosine signaling pathway, toll-4 (TLR4) receptors, and angiotensin II was reported in various tissues. Therefore, the aim of this study was to define the contribution of these two pathways to the hepatoprotective effects of telmisartan and/or chlorogenic acid (CGA) in NAFLD. CGA is a strong antioxidant that was previously reported to inhibit angiotensin converting enzyme. Male Wistar rats were treated with either high-fructose, with or without telmisartan, CGA, telmisartan + CGA for 8 weeks. Untreated NAFL rats showed characteristics of NAFLD, as evidenced by significant increase in the body weight, insulin resistance, and serum hepatotoxicity markers (Alanine and Aspartate transaminases) and lipids as compared to the negative control group, in addition to characteristic histopathological alterations. Treatment with either telmisartan and/or CGA improved aforementioned parameters, in addition to upregulation of antioxidant enzymes (Superoxide dismutase and Glutathione peroxidase). Effect of inhibiting RAS on both sphingosine pathway and TLR4 was evident by the suppressing effect of telmisartan and/or CGA on high fructose-induced upregulation of hepatic SPK1 and S1P, in addition to concomitant up-regulation of Sphingosine-1-Phosphate receptor (S1PR)3 protein level and increased expression of S1PR1 and TLR4. As TLR4 and SPK/S1P signaling pathways play important roles in the progression of liver inflammation, the effect on sphingosine pathway and TLR4 was associated with decreased concentrations of inflammatory markers, enzyme kB kinase (IKK), nuclear factor-kB and tumor necrosis factor-α as compared to untreated NAFL group. In conclusion, the present data strongly suggests the cross-talk between angiotensin, the Sphingosine SPK/S1P Axis and TLR4 Receptors, and their role in the pathogenesis of fructose-induced NAFLD, and the protection afforded by drugs inhibiting RAS.
肾素-血管紧张素-醛固酮系统（RAS）与非酒精性脂肪性肝病（NAFLD）有关；这是慢性肝病最常见的病因。越来越多的证据表明，改变的 TLR4 和鞘氨醇激酶 1（SphK1）/鞘氨醇 1 磷酸（S1P）信号通路是 NAFLD 发病机制中的关键因素。在各种组织中都有报道称，鞘氨醇信号通路、 toll-4（TLR4）受体和血管紧张素 II 之间存在串扰。因此，本研究的目的是确定这两条通路对替米沙坦和/或绿原酸（CGA）在 NAFLD 中肝保护作用的贡献。CGA 是一种很强的抗氧化剂，先前的研究表明它可以抑制血管紧张素转化酶。雄性 Wistar 大鼠用高果糖喂养 8 周，并用或不用替米沙坦、CGA、替米沙坦+ CGA 进行治疗。与阴性对照组相比，未经治疗的 NAFL 大鼠表现出 NAFLD 的特征，体重显著增加，胰岛素抵抗，血清肝毒性标志物（丙氨酸和天冬氨酸转氨酶）和脂质升高，此外还有特征性的组织病理学改变。用替米沙坦和/或 CGA 治疗可改善上述参数，同时上调抗氧化酶（超氧化物歧化酶和谷胱甘肽过氧化物酶）。替米沙坦和/或 CGA 对高果糖诱导的肝 SPK1 和 S1P 上调的抑制作用，以及同时上调 Sphingosine-1-Phosphate receptor（S1PR）3 蛋白水平和 TLR4 表达，表明抑制 RAS 对鞘氨醇途径和 TLR4 的影响。由于 TLR4 和 SPK/S1P 信号通路在肝脏炎症进展中发挥重要作用，因此与未经治疗的 NAFL 组相比，鞘氨醇途径和 TLR4 的作用与炎症标志物浓度的降低有关，包括酶 kB 激酶（IKK）、核因子-kB 和肿瘤坏死因子-α。总之，本研究数据强烈提示血管紧张素、鞘氨醇 SPK/S1P 轴和 TLR4 受体之间的串扰及其在果糖诱导的 NAFLD 发病机制中的作用，以及抑制 RAS 的药物提供的保护作用。
