Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Japan.
Neurogastroenterol Motil. 2020 May;32(5):e13799. doi: 10.1111/nmo.13799. Epub 2020 Jan 27.
The correlation of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) with non-alcoholic fatty liver disease (NAFLD) has been reported in epidemiological studies. However, the mechanisms of molecular and inter-organ systems that render these factors to influence on NAFLD have not been elucidated. In this study, we examined the induction of ghrelin which is the GH-releasing hormone and IGF-1, and involvement of autonomic neural circuits, in the pathogenesis of NAFLD.
The expression of gastric and hypothalamic ghrelin, neural activation in the brain, and serum IGF-1 were examined in NAFLD models of choline-deficient defined l-amino-acid diet-fed, melanocortin 4 receptor knockout mice, and partial hepatectomy mice with or without the blockades of autonomic nerves to test the contribution of neural circuits connecting the brain, liver, and stomach.
The fatty changes in the liver increased the expression of gastric ghrelin through the autonomic pathways which sends the neural signals to the arcuate nucleus in the hypothalamus through the afferent vagal nerve which reached the pituitary gland to release GH and then stimulate the IGF-1 release from the liver. In addition, high levels of ghrelin expression in the arcuate nucleus were correlated with NAFLD progression regardless of the circuits.
Our study demonstrated that the fatty liver stimulates the autonomic nervous signal circuits which suppress the progression of the disease by activating the gastric ghrelin expression, the neural signal transduction in the brain, and the release of IGF-1 from the liver.
生长激素（GH）和胰岛素样生长因子-1（IGF-1）与非酒精性脂肪性肝病（NAFLD）的相关性已在流行病学研究中报道。然而，这些因素影响 NAFLD 的分子和器官间系统的机制尚未阐明。在这项研究中，我们研究了促胃液素（ghrelin）的诱导作用，ghrelin 是一种释放 GH 的激素，以及自主神经回路的参与，在 NAFLD 的发病机制中。
在胆碱缺乏型定义的氨基酸饮食喂养、黑皮质素 4 受体敲除小鼠和部分肝切除小鼠的 NAFLD 模型中，检测了胃和下丘脑 ghrelin 的表达、大脑中的神经激活以及血清 IGF-1 的表达，以测试连接大脑、肝脏和胃的神经回路的贡献。
肝脏的脂肪变化通过自主途径增加了胃 ghrelin 的表达，该途径通过传入迷走神经将神经信号发送到下丘脑的弓状核，到达垂体释放 GH，然后刺激肝脏释放 IGF-1。此外，无论回路如何，弓状核中 ghrelin 表达水平升高与 NAFLD 进展相关。
我们的研究表明，脂肪肝通过激活胃 ghrelin 表达、大脑中的神经信号转导以及肝脏释放 IGF-1，刺激自主神经信号通路，从而抑制疾病的进展。
