Department of Gastroenterology, University of Tsukuba, Tsukuba, Japan.
Hepatol Res. 2009 May;39(5):490-500. doi: 10.1111/j.1872-034X.2008.00478.x. Epub 2009 Jan 16.
Sequestosome 1 (SQSTM1)/A170/p62 plays an important role in membrane-receptor mediated signal transduction and autophagic protein degradation. Although the mechanism involved is not clear, sqstm1 gene knockout (KO) mice develop mature-onset obesity and insulin resistance, leading to type II diabetes. KO mice show accumulation of fat in white adipose tissue and the liver when fed a standard diet. Acarbose is an alpha-glucosidase inhibitor that improves insulin sensitivity and decreases postprandial hyperglycemia, and it is used to treat type 2 diabetes. We examined whether or not dietary acarbose prevented obesity and simple steatosis in KO mice.
Wild-type (WT) and KO mice were fed a standard diet with or without acarbose (0.8% w/w) from 15-25 weeks of age. The body weight and the fat content of adipose tissue and the liver were measured, and changes of lipid metabolism in these tissues were assessed from gene expression.
Acarbose treatment suppressed weight gain and the development of hepatic steatosis in KO mice. Acarbose treatment up-regulated hepatic expression of the pparalpha, ucp-2, and abca1 genes, as well as srebp1c, pparalpha, and ppargamma in adipose tissue. In WT mice, however, acarbose treatment had little influence on weight gain and gene expression.
The results of this study suggest that long-term administration of acarbose is effective for prevention of obesity and simple steatosis in SQSTM1-KO mice.
自噬相关蛋白 1（SQSTM1）/A170/p62 在膜受体介导的信号转导和自噬蛋白降解中发挥重要作用。虽然其机制尚不清楚，但 SQSTM1 基因敲除（KO）小鼠会发展为成年发病型肥胖和胰岛素抵抗，导致 II 型糖尿病。KO 小鼠在标准饮食喂养下会在白色脂肪组织和肝脏中积累脂肪。阿卡波糖是一种α-葡萄糖苷酶抑制剂，可改善胰岛素敏感性并降低餐后高血糖，用于治疗 2 型糖尿病。我们研究了饮食中添加阿卡波糖是否可以预防 KO 小鼠肥胖和单纯性脂肪变性。
15-25 周龄的野生型（WT）和 KO 小鼠分别用标准饮食或添加 0.8% w/w 阿卡波糖的标准饮食喂养。测量体重和脂肪组织及肝脏中的脂肪含量，并从基因表达评估这些组织中脂质代谢的变化。
阿卡波糖治疗抑制了 KO 小鼠的体重增加和肝脂肪变性。阿卡波糖治疗上调了肝脏中 pparalpha、UCP-2 和 ABCA1 基因以及脂肪组织中 SREBP1C、PPARalpha 和 PPARgamma 的表达。然而，在 WT 小鼠中，阿卡波糖治疗对体重增加和基因表达几乎没有影响。
本研究结果表明，长期给予阿卡波糖可有效预防 SQSTM1-KO 小鼠肥胖和单纯性脂肪变性。
