Role of Aramchol in steatohepatitis and fibrosis in mice.
Role of Aramchol in steatohepatitis and fibrosis in mice.
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DOI：
10.1002/hep4.1107
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发表时间：
2017-11
影响因子：
5.1
通讯作者：
Mato JM
中科院分区：
文献类型：
--
作者：
Iruarrizaga-Lejarreta M;Varela-Rey M;Fernández-Ramos D;Martínez-Arranz I;Delgado TC;Simon J;Juan VG;delaCruz-Villar L;Azkargorta M;Lavin JL;Mayo R;Van Liempd SM;Aurrekoetxea I;Buqué X;Cave DD;Peña A;Rodríguez-Cuesta J;Aransay AM;Elortza F;Falcón-Pérez JM;Aspichueta P;Hayardeny L;Noureddin M;Sanyal AJ;Alonso C;Anguita J;Martínez-Chantar ML;Lu SC;Mato JM
非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病（NAFLD）的晚期形式，为进一步的肝损伤奠定了基础。NASH进展的机制涉及多个平行打击，包括氧化应激、线粒体功能障碍、炎症等。操纵这些途径中的任何一种都可能是预防NASH发展和进展的方法。花生酰氨基胆烷酸（Aramchol）目前处于IIb期NASH研究中。本研究的目的是使用NASH的蛋氨酸和胆碱缺乏（MCD）饮食模型研究Aramchol的作用机制及其对纤维化的影响。我们采集了喂食含0.1%蛋氨酸（0.1 MCD）MCD饲料4周的小鼠的肝脏和血清;这些小鼠发生了脂肪性肝炎和纤维化。我们还收集了接受对照饮食的小鼠的肝脏和血清，并测定了两组的代谢组和蛋白质组。对喂食0.1 MCD的小鼠给予Aramchol（5 mg/kg/天，最后2周），并对肝脏样本进行组织学分析。Aramchol给药减少了喂食0.1 MCD的小鼠的脂肪性肝炎和纤维化特征。Aramchol下调硬脂酰辅酶A去饱和酶1，这是一种参与甘油三酯生物合成的关键酶，其损失会增强脂肪酸β氧化。Aramchol增加了通过转硫途径的通量，导致谷胱甘肽（GSH）和GSH/氧化型GSH比率升高，GSH是维持细胞内氧化还原状态的主要细胞抗氧化剂。0.1 MCD喂养小鼠与NAFLD患者之间的血清代谢组学模式比较显示存在大量重叠。结论：Aramchol治疗通过以下方式改善脂肪性肝炎和纤维化：1）减少硬脂酰辅酶A去饱和酶1和2）增加通过转硫途径的通量，维持细胞氧化还原稳态。我们还证明，0.1MCD模型类似于在约50%的NAFLD患者中观察到的代谢表型，这支持Aramchol在NASH治疗中的潜在用途。（Hepatology Communications 2017;1：911-927）
Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatology Communications 2017;1:911–927)
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影响因子：
16.6
作者：
Eriksson, Sofi;Prigge, Justin R.;Talago, Emily A.;Arner, Elias S. J.;Schmidt, Edward E.
通讯作者：
Schmidt, Edward E.
影响因子：
25.7
作者：
Medici, Valentina;Peerson, Janet M.;Stabler, Sally P.;French, Samuel W.;Gregory, Jesse F., III;Virata, Maria Catrina;Albanese, Antony;Bowlus, Christopher L.;Devaraj, Sridevi;Panacek, Edward A.;Rahim, Nazir;Richards, John R.;Rossaro, Lorenzo;Halsted, Charles H.
通讯作者：
Halsted, Charles H.
影响因子：
4.8
作者：
Li, Zheng Zheng;Berk, Michael;Feldstein, Ariel E.
通讯作者：
Feldstein, Ariel E.
人类脂肪肝病：旧问题和新见解。
DOI：
10.1126/science.1204265
发表时间：
2011-06-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cohen JC;Horton JD;Hobbs HH
通讯作者：
Hobbs HH
DOI：
10.1073/pnas.132384699
发表时间：
2002-08-20
影响因子：
11.1
作者：
Ntambi, JM;Miyazaki, M;Attie, AD
通讯作者：
Attie, AD