Ariyasu Hiroyuki, Yamada Go, Iwakura Hiroshi, Akamizu Takashi, Kangawa Kenji, Nakao Kazuwa
Department of Endocrinology and Metabolism, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Methods Enzymol. 2012;514:371-7. doi: 10.1016/B978-0-12-381272-8.00023-4.
To understand the chronic effects of ghrelin, genetically engineered mouse models would be useful. Early studies, however, suggested that it was challenging to generate ghrelin gain-of-activity models by standard procedures. Although several groups have been trying to generate transgenic (Tg) mice overexpressing ghrelin, almost all these animals produced only des-acyl ghrelin rather than acylated ghrelin. Therefore, to elucidate the mechanism for the fatty acid modification in ghrelin, many researchers have been seeking an enzyme that would catalyze the acylation of ghrelin with an octanoic acid. In 2008, ghrelin O-acyltransferase (GOAT) was identified at last, and thereafter double-Tg mice overexpressing ghrelin and GOAT were generated by Kirchner et al. On the other hand, we have succeeded in generating Tg mice overexpressing Trp(3)-ghrelin, a ghrelin analog that does not require posttranscriptional modification with GOAT for activity. These ghrelin gain-of-activity models are useful tools for evaluating the long-term pathophysiological and/or pharmacological effects of ghrelin or ghrelin analogs and provide insight into the physiological roles of ghrelin/GHS-R systems.
为了解胃饥饿素的慢性影响，基因工程小鼠模型会很有用。然而，早期研究表明，通过标准程序生成胃饥饿素活性增强模型具有挑战性。尽管有几个研究小组一直在尝试培育过表达胃饥饿素的转基因（Tg）小鼠，但几乎所有这些动物只产生去酰基胃饥饿素，而非酰化胃饥饿素。因此，为阐明胃饥饿素中脂肪酸修饰的机制，许多研究人员一直在寻找一种能催化胃饥饿素与辛酸酰化的酶。2008年，胃饥饿素O-酰基转移酶（GOAT）终于被鉴定出来，此后，Kirchner等人培育出了过表达胃饥饿素和GOAT的双转基因小鼠。另一方面，我们成功培育出了过表达Trp(3)-胃饥饿素的转基因小鼠，Trp(3)-胃饥饿素是一种胃饥饿素类似物，其活性不需要GOAT进行转录后修饰。这些胃饥饿素活性增强模型是评估胃饥饿素或胃饥饿素类似物的长期病理生理和/或药理作用的有用工具，并能深入了解胃饥饿素/GHS-R系统的生理作用。
