The mTOR-ETV5 signaling in gastric X/A like cells and its role in hepatic lipid metabolism and steatosis

胃X/A样细胞中的mTOR-ETV5信号及其在肝脂质代谢和脂肪变性中的作用

• 批准号: 10274428
• 负责人: Weizhen Zhang
• 金额: $ 60.03万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274428
• 关键词: Acylation; Acyltransferase; Adult; Affect; American; Binding; Biological; Body Weight decreased; Cells; Cirrhosis; Data; Deposition; Development; Eating; Event; FRAP1 gene; Fatty Liver; Food Intake Regulation; GHS-R1a; Gene Expression; Genes; Goals; Health; Hepatic; Hepatocyte; High Fat Diet; Hormones; Hypothalamic structure; Kupffer Cells; Lipids; Liver; Mediating; Modification; Mus; Names; Neurons; Nutrient; Obesity; Organism; Pathogenesis; Pathway interactions; Primary carcinoma of the liver cells; Production; Regulation; Role; Signal Pathway; Signal Transduction; Site; Societies; Steatohepatitis; Stomach; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; Triglycerides; Variant; des-n-octanoyl ghrelin; design; energy balance; ghrelin; growth hormone secretagogue receptor; insight; lipid metabolism; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; transcription factor; treatment strategy

Our preliminary studies have identified a novel stomach-liver humoral axis. Mechanistic target of rapamycin (mTOR) signaling pathway in the gastric X/A like cells coordinates nutrient availability with the hepatic lipid metabolism via ghrelin. Our studies have also identified ETV5, an ETS-related transcriptional factor, as the novel downstream target of mTOR signaling. Further, ETV5 alters the expression of ghrelin O-acyltransferase and subsequent acylation of ghrelin. Although X/A like cells in the stomach produce and secrete both acyl- and desacyl-ghrelin, only acyl-ghrelin binds and activates its receptor: growth hormone secretagogue receptor 1a (GHSR1a). Acyl-ghrelin was originally demonstrated to act via the hypothalamus to stimulate food intake. Our data now indicate that acyl-ghrelin regulates hepatic lipid synthesis via its direct action on hepatocytes. We thus propose four aims to investigate the functions of gastric mTOR-ETV5 signaling pathway in the production and secretion of acyl-ghrelin and its effects on hepatic lipid metabolism. Aim 1 will establish ETV5 as the downstream target of mTOR, mediating its unique regulation of ghrelin acylation in X/A like cells. Aim 2, using transgenic mice in which mTOR signaling in gastric X/A like cells is either activated or suppressed, will demonstrate that gastric mTOR signaling affects hepatic lipid metabolism and the development of hepatic steatosis induced by a high-fat diet. Aim 3 will examine whether ETV5 in gastric X/A like cells alters hepatic lipid metabolism and the development of hepatic steatosis induced by a high-fat diet, using mice in which ETV5 gene expression in gastric X/A like cells is altered. Aim 4 will determine whether acyl-ghrelin mediates the effects of gastric mTOR on hepatic lipid metabolism via its activation of GHSR1a on hepatocytes, Kupffer cells and/or hypothalamic (HTH) neurons. We will use cell biological and transgenic techniques to achieve these goals. Completion of this proposal will advance a completely new therapeutic approach for NAFLD, one directed at gastric sites.

我们的初步研究已经确定了一个新型的胃肝体液轴。胃X/A相似细胞中雷帕霉素（MTOR）信号通路的机理靶标可通过生长素蛋白与肝脂质代谢相协调养分。我们的研究还确定了ETV5（ETS相关的转录因子）是MTOR信号传导的新型下游靶标。此外，ETV5改变了生长素蛋白O-酰基转移酶的表达以及随后的生长素蛋白的表达。尽管胃中的X/A类细胞会产生并分泌酰基 - 甲状腺元素蛋白，但只有酰基 - ghrelin结合并激活其受体：生长激素秘密受体受体1A（GHSR1A）。最初证明了酰基糖蛋白可以通过下丘脑起作用以刺激食物摄入量。现在，我们的数据表明，酰基糖蛋白通过其直接作用对肝细胞调节肝脂质合成。因此，我们提出了四个旨在研究胃MTOR-ETV5信号传导途径在酰基ghrelin及其对肝脂质代谢的影响中的功能。 AIM 1将建立ETV5作为MTOR的下游靶标，从而介导其在X/A类细胞中的生长素蛋白酰基化的独特调节。 AIM 2使用转基因小鼠激活或抑制胃中的MTOR信号传导，将证明胃MTOR信号传导会影响肝脂质代谢和高脂饮食诱导的肝脂肪变性的发展。 AIM 3将检查胃X/A类中的ETV5是否使用高脂饮食诱导的肝脂质代谢以及使用胃X/A类似细胞中ETV5基因表达的小鼠的肝脂肪变性的发展。 AIM 4将通过其激活GHSR1A对肝细胞，kupffer细胞和/或下丘脑（HTH）神经元的激活来介导胃mTOR对肝脂质代谢的影响。我们将使用细胞生物学和转基因技术来实现这些目标。该提案的完成将推进NAFLD的全新治疗方法，该方法针对胃站点。