Namisaki Tadashi, Moriya Kei, Kitade Mitsuteru, Takeda Kosuke, Kaji Kosuke, Okura Yasushi, Shimozato Naotaka, Sato Shinya, Nishimura Norihisa, Seki Kenichiro, Kawaratani Hideto, Takaya Hiroaki, Sawada Yasuhiko, Akahane Takemi, Saikawa Soichiro, Nakanishi Keisuke, Kubo Takuya, Furukawa Masanori, Noguchi Ryuichi, Asada Kiyoshi, Kitagawa Koh, Ozutsumi Takahiro, Tsuji Yuki, Kaya Daisuke, Fujinaga Yukihisa, Yoshiji Hitoshi
Third Department of Internal Medicine Nara Medical University Kashihara Japan.
Hepatol Commun. 2017 Sep 19;1(9):928-945. doi: 10.1002/hep4.1104. eCollection 2017 Nov.
The farnesoid X receptor (FXR) agonist, a bile acid-activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1 mL/kg pig serum (PS) twice a week, whereas Fischer-344 rats were fed a choline-deficient, L-amino acid-defined diet (CDAA). The and effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS-administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor β1 and toll-like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens-1 disruption, whereas losartan directly suppressed activated-HSC (Ac-HSC) regulation. The inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor β1, toll-like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor-κB and mothers against decapentaplegic homolog 3 in Ac-HSC were almost in parallel. Losartan directly inhibited the regulation of Ac-HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS-administered OLETF and CDAA-treated rats. : INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac-HSC proliferation. Combined therapy may represent a promising novel approach for NASH. ( 2017;1:928-945).
法尼酯X受体（FXR）激动剂是一种胆汁酸激活的核受体，已被证明可改善非酒精性脂肪性肝炎（NASH）的组织学特征；然而，对肝纤维化尚未取得令人满意的效果。我们旨在研究FXR激动剂和血管紧张素II 1型受体阻滞剂对NASH大鼠模型肝纤维化形成的联合作用。持续8周，建立了两种NASH大鼠模型。大冢长-艾氏-德岛肥胖（OLETF）大鼠每周两次腹腔注射1 mL/kg猪血清（PS），而Fischer-344大鼠喂食胆碱缺乏、L-氨基酸限定饮食（CDAA）。评估了FXR激动剂（INT747）和血管紧张素II 1型受体阻滞剂（氯沙坦）对肝纤维化形成的作用和效果。在注射PS的OLETF大鼠中，INT747和氯沙坦对肝纤维化形成具有强效抑制作用，可抑制肝星状细胞（HSC）激活以及转化生长因子β1和Toll样受体4的表达。INT747通过改善紧密连接蛋白-1的破坏降低肠道通透性，而氯沙坦直接抑制活化的HSC（Ac-HSC）调控。INT747和氯沙坦对Ac-HSC中转化生长因子β1、Toll样受体4和髓样分化因子88的信使核糖核酸表达以及核因子-κB和果蝇母体效应基因3磷酸化的抑制作用几乎是平行的。氯沙坦直接抑制Ac-HSC的调控。同样，INT747与氯沙坦联合使用对喂食CDAA饮食的大鼠的肝纤维化形成有益。在注射PS的OLETF大鼠和接受CDAA治疗的大鼠中，这些药物的治疗效果几乎相当。结论：INT747和氯沙坦通过逆转肠道屏障功能障碍和抑制Ac-HSC增殖协同抑制肝纤维化形成。联合治疗可能是一种有前景的NASH新方法。（《》2017；1：928 - 945）
