Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
J Hepatol. 2010 Jun;52(6):903-12. doi: 10.1016/j.jhep.2009.12.033. Epub 2010 Mar 24.
BACKGROUND & 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.
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.
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.
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.
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,它包含了广泛的实体,从单纯的肝脂肪变性到非酒精性脂肪性肝炎(NASH)。然而,由于缺乏自发性 NASH 动物模型,这阻碍了该领域的基础研究。
我们检查了具有 2 型糖尿病的近交 Fatty Liver Shionogi(FLS)小鼠的肝损伤,并研究了导致 NAFLD/NASH 的分子机制。使用微体甘油三酯转移蛋白(MTP)的载体介导的肝表达,MTP 是极低密度脂蛋白(VLDL)组装和输出的关键分子,研究了其对肝损伤以及葡萄糖不耐受的贡献。
在正常饮食条件下维持的 FLS 小鼠由于 VLDL 分泌受损而表现出过多的肝甘油三酯(TG)积累,随后出现类似于 NASH 的肝损伤,炎症分子以及胰岛素抵抗的表达增加。基因表达和 Western blot 分析表明,FLS 小鼠的肝 MTP 表达减少。肝 MTP 的诱导导致肝 TG 积累减少,VLDL 输出改善,NASH 样病变以及葡萄糖不耐受得到改善。
这些数据表明,FLS 小鼠可能是一种具有胰岛素抵抗的自发性 NASH 模型,并且 MTP 减少参与了 NASH 的发生,提示 MTP 是预防和治疗 NASH 的关键靶点。