Role of Aramchol in steatohepatitis and fibrosis in mice
| العنوان: | Role of Aramchol in steatohepatitis and fibrosis in mice |
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| المؤلفون: | Juan Rodríguez-Cuesta, María L. Martínez-Chantar, Ana M. Aransay, Ibon Martínez-Arranz, José M. Mato, José Luis Lavín, Virginia Gutiérrez-de Juan, Jorge Simón, Mikel Azkargorta, Patricia Aspichueta, Rebeca Mayo, Juan Anguita, Mazen Noureddin, Arantza Peña, Laura delaCruz-Villar, Juan M. Falcón-Pérez, Liat Hayardeny, Sebastiaan M. Van Liempd, Igor Aurrekoetxea, Cristina Alonso, David Fernández-Ramos, Marta Varela-Rey, Felix Elortza, Xabier Buqué, Teresa C. Delgado, Marta Iruarrizaga-Lejarreta, Arun J. Sanyal, Shelly C. Lu, Donatella Delle Cave |
| المصدر: | Hepatology Communications Hepatology communications, vol 1, iss 9 |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.medical_specialty, Chronic Liver Disease and Cirrhosis, Transsulfuration pathway, Biology, medicine.disease_cause, Oral and gastrointestinal, Mouse model, Hepatitis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Internal medicine, Nonalcoholic fatty liver disease, medicine, Nutrition, S-adenosylmethionine, Methionine, Hepatology, Liver Disease, nutritional and metabolic diseases, Lipid metabolism, Glutathione, Original Articles, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, chemistry, 1-carbon metabolism, 030211 gastroenterology & hepatology, Original Article, Steatohepatitis, Digestive Diseases, Oxidative stress |
| الوصف: | 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) |
| وصف الملف: | application/pdf |
| تدمد: | 2471-254X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66d61427c5b7e668ff75cac7f375f89bTest https://pubmed.ncbi.nlm.nih.gov/29159325Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....66d61427c5b7e668ff75cac7f375f89b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2471254X |
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