Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
Department of Pharmacology and Toxicology, National Research Centre, Giza, Egypt.
Inflammation. 2019 Jun;42(3):1056-1070. doi: 10.1007/s10753-019-00967-6.
The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.
非酒精性脂肪性肝炎（NASH）是最常见的肝脏疾病，其特征为肝脂肪变性和炎症伴有肝细胞损伤。最近，它可能成为肝移植的主要原因。由于缺乏治疗 NASH 的批准药物，因此研究沙格列汀（SAR）很有必要，最近的研究表明，SAR 作为一种双重过氧化物酶体增殖物激活受体-α/γ激动剂，对 NASH 有良好的疗效。在这里，我们旨在研究 SAR 对高脂肪乳剂（HFE）和小剂量脂多糖（LPS）给药 5 周诱导的 NASH 大鼠的影响。大鼠分为三组：阴性对照组（生理盐水和标准啮齿动物饲料）、模型组（HFE(10ml/kg/天，口服灌胃) + LPS(0.5mg/kg/周，腹腔注射)）和 SAR 治疗组（HFE(10ml/kg/天，口服灌胃) + LPS(0.5mg/kg/周，腹腔注射) + SAR(4mg/kg/天，口服灌胃)，从第 3 周开始）。SAR 治疗成功地减轻了 HFE 和 LPS 的损伤作用，通过对抗体重增加和生化指标（肝功能参数、葡萄糖、胰岛素、稳态模型评估（HOMA-IR）评分、血脂谱水平）的正常化来实现。观察到脂肪因子水平的显著变化，导致血清瘦素和肿瘤坏死因子-α（TNF-α）水平显著下降，同时瘦素和肿瘤坏死因子-α（TNF-α）水平显著下降，而脂联素水平正常化。SAR 对 NASH 的积极影响归因于 LPS/TLR4 通路的下调，表现为肝 Toll 样受体 4（TLR4）、NF-κB、TNF-α 和转化生长因子-β1（TGF-β1）表达的抑制。总之，这项工作验证了 SAR 通过失活肝 LPS/TLR4 通路和抑制脂肪细胞功能障碍来改善 NASH。
