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: 10414996
• 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/10414996
• 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的胃-肝体液轴。在胃X/A样细胞中的雷帕霉素（mTOR）信号通路的机制靶标通过ghrelin协调营养利用与肝脏脂质代谢。我们的研究还确定了ETV 5，一种ETS相关的转录因子，作为mTOR信号转导的新下游靶点。此外，ETV 5改变生长素释放肽O-酰基转移酶的表达和随后的生长素释放肽酰化。虽然胃中的X/A样细胞产生并分泌酰基-和去酰基-ghrelin，但只有酰基-ghrelin结合并激活其受体：生长激素促分泌素受体1a（GHSR 1a）。酰基饥饿素最初被证明通过下丘脑刺激食物摄入。我们的数据表明，酰基-生长激素释放肽通过其对肝细胞的直接作用来调节肝脏脂质合成。因此，我们提出了四个目的，以研究胃mTOR-ETV 5信号通路在酰基-ghrelin的产生和分泌中的功能及其对肝脏脂质代谢的影响。目的1将ETV 5作为mTOR的下游靶点，介导其在X/A样细胞中对ghrelin酰化的独特调节。目的2，使用胃X/A样细胞中mTOR信号被激活或抑制的转基因小鼠，将证明胃mTOR信号影响肝脏脂质代谢和高脂饮食诱导的肝脂肪变性的发展。目的3将使用胃X/A样细胞中ETV 5基因表达改变的小鼠来检查胃X/A样细胞中ETV 5是否改变肝脏脂质代谢和由高脂饮食诱导的肝脂肪变性的发展。目的4将确定酰基-ghrelin是否通过其激活肝细胞、枯否细胞和/或下丘脑（HTH）神经元上的GHSR 1a来介导胃mTOR对肝脏脂质代谢的影响。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，一种针对胃部位的治疗方法。