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.

我们的初步研究发现了一个新的胃-肝脏体液轴。胃X/A样细胞中雷帕霉素(MTOR)信号通路的机械靶点通过Ghrelin调节营养物质的供应和肝脏的脂肪代谢。我们的研究还确定ETV5是一种与ETS相关的转录因子，是mTOR信号转导的新下游靶点。此外，ETV5还改变了Ghrelin O-酰基转移酶的表达和随后的Ghrelin的酰化。虽然胃中的X/A样细胞同时产生和分泌酰基和去脂基-ghrelin，但只有酰基-ghrelin结合和激活其受体：生长激素促分泌素受体1a(GHSR1a)。酰基胃促生长素最初被证明是通过下丘脑来刺激食物摄入的。我们的数据现在表明，酰基-Ghrelin通过直接作用于肝细胞来调节肝脏脂质的合成。因此，我们提出了四个目标，以研究胃mTOR-ETV5信号通路在酰基-Ghrelin产生和分泌中的作用及其对肝脂代谢的影响。目的1将ETV5确定为mTOR的下游靶点，介导其对X/A样细胞中Ghrelin酰化的独特调节。目的2利用胃X/A样细胞mTOR信号被激活或被抑制的转基因小鼠，证实胃mTOR信号影响高脂饮食诱导的肝脏脂代谢和肝脏脂肪变性的发生。目的利用胃X/A样细胞ETV5基因表达改变的小鼠模型，研究胃X/A样细胞中ETV5基因的表达是否改变了高脂饮食所致的肝脏脂代谢和肝脂肪变性的发生。目的4将确定酰基-Ghrelin是否通过激活肝细胞、Kupffer细胞和/或下丘脑(HTH)神经元上的GHSR1a来介导胃mTOR对肝脂代谢的影响。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一种针对胃部位的治疗NAFLD的全新方法。