Institut Pasteur de Lille, Lille, France; Inserm, UMR1011, Lille, France; Université Lille Nord de France, Lille, France; Université Droit et Santé de Lille, Lille, France.
Hepatology. 2013 Dec;58(6):1941-52. doi: 10.1002/hep.26461. Epub 2013 Oct 29.
Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4 -induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase.
The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms.
非酒精性脂肪性肝病（NAFLD）涵盖了从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH）、纤维化和肝硬化等一系列肝脏损伤。迄今为止，尚无批准用于 NAFLD/NASH 的药物治疗。在这里，我们报告了一种新型双重过氧化物酶体增殖物激活受体α/δ（PPAR-α/δ）激动剂 GFT505 的临床前和临床数据。在大鼠中，GFT505 集中在肝脏中，肝外暴露有限，并经历广泛的肠肝循环。在 NAFLD/NASH 和肝纤维化的动物模型中评估了 GFT505 的疗效（西方饮食[WD]喂养的人载脂蛋白 E2 [hApoE2]转基因小鼠、蛋氨酸和胆碱缺乏饮食喂养的 db/db 小鼠和 CCl4 诱导的大鼠纤维化）。GFT505 对脂肪变性、炎症和纤维化具有肝脏保护作用。此外，GFT505 改善了肝功能标志物，减少了肝脂质堆积，并抑制了促炎（白细胞介素-1β、肿瘤坏死因子-α和 F4/80）和促纤维化（转化生长因子-β、金属蛋白酶 2 组织抑制剂、胶原 I、α1 和胶原 I、α2）基因表达。为了确定 PPAR-α 独立机制的作用，评估了 GFT505 在 hApoE2 敲入/PPAR-α 敲除小鼠中的作用。在这些小鼠中，GFT505 还可预防 WD 诱导的肝脂肪变性和炎症，表明存在 PPAR-α 独立机制的作用。最后，在代谢综合征患者的四项 II 期临床研究的综合分析中评估了 GFT505 对肝功能标志物的影响。GFT505 治疗降低了丙氨酸氨基转移酶、γ-谷氨酰转肽酶和碱性磷酸酶的血浆浓度。
双重 PPAR-α/δ 激动剂 GFT505 是一种有前途的治疗 NAFLD/NASH 的肝脏靶向药物。在动物中，其保护作用是由 PPAR-α 依赖性和非依赖性机制介导的。
