Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model
Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model
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DOI：
10.1016/j.jhep.2009.12.033
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发表时间：
2010-06-01
影响因子：
25.7
通讯作者：
Rakugi, Hiromi
中科院分区：
文献类型：
--
作者：
Shindo, Nobuyasu;Fujisawa, Tomomi;Rakugi, Hiromi
背景八：目的：非酒精性脂肪性肝病（NAFLD）目前被认为是一个全球性的健康问题，包括广泛的实体，从单纯性脂肪肝到非酒精性脂肪性肝炎（NASH）。缺乏一个自发的动物模型NASH，但是，阻碍了基础研究在这一领域。方法：我们研究了在近交系脂肪肝Shionogi（FLS）小鼠，表现出2型糖尿病的肝脏病变，并研究了导致NAFLD/NASH的分子机制。使用载体介导的微粒体甘油三酯转移蛋白（MTP）的肝脏表达，微粒体甘油三酯转移蛋白是极低密度脂蛋白（VLDL）组装和输出的关键分子，其对肝脏病变以及葡萄糖耐受不良的贡献被检查。维持正常食物的FLS小鼠由于VLDL分泌受损而表现出过度的肝脏甘油三酯（TG）积累，随后表现出与NASH相当的肝脏病变，炎症分子的表达增加以及胰岛素抵抗。基因表达和蛋白质印迹分析表明FLS小鼠中MTP的肝脏表达减少。肝脏诱导MTP可减少肝脏TG积聚，改善VLDL输出，改善NASH样病变以及葡萄糖不耐受。结论：这些数据表明FLS小鼠可作为NASH伴胰岛素抵抗的自发模型，并且降低的MTP参与了NASH的发生，表明MTP是预防和治疗NASH的关键靶点。(c)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background 8: Aims: Nonalcoholic fatty liver disease (NAFLD) is currently recognized as a global health issue and encompasses a wide spectrum of entities, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). The lack of a spontaneous animal model of NASH, however, has hampered basic research in this field.Methods: We examined the hepatic lesions in the inbred Fatty Liver Shionogi (FLS) mouse, which exhibits type 2 diabetes, and investigated the molecular mechanism leading to NAFLD/NASH. Using vector-mediated hepatic expression of microsomal triglyceride transfer protein (MTP), a key molecule for very low density lipoprotein (VLDL) assembly and export, its contribution to the hepatic lesions as well as to glucose intolerance was examined.Results: The FLS mouse, maintained on normal chow, exhibited excessive hepatic triglyceride (TG) accumulation due to impaired VLDL secretion, and subsequently hepatic lesions comparable to NASH, with increased expression of inflammatory molecules as well as insulin resistance. Gene expression and Western blot analyses demonstrated reduced hepatic expression of MTP in the FLS mouse. Hepatic induction of MTP resulted in a reduction in hepatic TG accumulation, improvement of VLDL export, and amelioration of NASH-like lesions, as well as glucose intolerance.Conclusions: These data suggest that the FLS mouse could serve as a spontaneous model of NASH with insulin resistance, and that reduced MTP is involved in the development of NASH, pointing towards MTP as a critical target for the prevention and treatment of NASH. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.