Wettstein Guillaume, Luccarini Jean-Michel, Poekes Laurence, Faye Patrick, Kupkowski Francine, Adarbes Vanessa, Defrêne Evelyne, Estivalet Céline, Gawronski Xavier, Jantzen Ingrid, Philippot Alain, Tessier Julien, Tuyaa-Boustugue Pascale, Oakley Fiona, Mann Derek A, Leclercq Isabelle, Francque Sven, Konstantinova Irena, Broqua Pierre, Junien Jean-Louis
Inventiva Daix France.
Pôle d'Hépato-gastro-entérologie, Université Catholique de Louvain Bruxelles Belgium.
Hepatol Commun. 2017 Jun 19;1(6):524-537. doi: 10.1002/hep4.1057. eCollection 2017 Aug.
IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet-induced obesity model (high-fat/high-sucrose diet); a methionine- and choline-deficient diet; the foz/foz model; the CCl-induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β-oxidation-related and fatty acid desaturation-related genes in both the methionine- and choline-deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. : The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. ( 2017;1:524-537).
IVA337是一种泛过氧化物酶体增殖物激活受体（PPAR）激动剂，对三种PPAR亚型（α、γ、δ）具有适度且平衡良好的活性。PPAR是脂质代谢、炎症、胰岛素抵抗和纤维化形成的调节因子。不同的单一或双重PPAR激动剂已被研究其在非酒精性脂肪性肝炎（NASH）中的治疗潜力，NASH是一种慢性肝脏疾病，脂肪变性与坏死性炎症并存，可能导致肝纤维化和肝硬化。临床结果表明，根据所测试药物的特性，组织学评估的肝脏病变有不同程度的改善，这表明同时激活三种PPAR亚型可能会为NASH患者带来更显著的治疗效果。我们研究了IVA337对几种重现与NASH相关的主要代谢和肝脏特征的临床前模型的影响。这些模型包括饮食诱导的肥胖模型（高脂肪/高蔗糖饮食）；蛋氨酸和胆碱缺乏饮食；foz/foz模型；CCl诱导的肝纤维化模型（预防性和治疗性）以及人原代肝星状细胞。IVA337使胰岛素敏感性正常化，同时控制体重增加、肥胖指数和血清甘油三酯升高；它降低了肝脏脂肪变性、炎症和气球样变。IVA337在CCl模型中对纤维化表现出预防和治疗作用，并抑制人肝星状细胞的增殖和激活，肝星状细胞是NASH中驱动肝纤维化的关键细胞。此外，在蛋氨酸和胆碱缺乏饮食以及foz/foz模型中，IVA337抑制了（促）纤维化和炎性小体基因的表达，同时增加了β-氧化相关和脂肪酸去饱和相关基因的表达。对于所有模型，IVA337显示出优于选择性PPARα、PPARδ或PPARγ激动剂的抗纤维化功效。我们的数据支持IVA337治疗NASH患者的治疗潜力。（2017；1：524 - 537）
