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.

我们的初步研究发现了一种新的胃-肝体液轴。胃 X/A 样细胞中雷帕霉素 (mTOR) 信号通路的机制靶标通过生长素释放肽协调营养可用性与肝脏脂质代谢。我们的研究还发现 ETV5（一种 ETS 相关转录因子）是 mTOR 信号传导的新下游靶点。此外，ETV5 改变生长素释放肽 O-酰基转移酶的表达以及随后生长素释放肽的酰化。尽管胃中的 X/A 样细胞产生并分泌酰基和去酰基生长素释放肽，但只有酰基生长素释放肽结合并激活其受体：生长激素促分泌素受体 1a (GHSR1a)。酰基生长素释放肽最初被证明可以通过下丘脑刺激食物摄入。我们的数据现在表明酰基生长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，我们提出四个目标来研究胃mTOR-ETV5信号通路在酰基生长素释放肽的产生和分泌中的功能及其对肝脏脂质代谢的影响。目标 1 将建立 ETV5 作为 mTOR 的下游靶标，介导其对 X/A 样细胞中生长素释放肽酰化的独特调节。目标 2，使用胃 X/A 样细胞中 mTOR 信号传导被激活或抑制的转基因小鼠，将证明胃 mTOR 信号传导影响肝脏脂质代谢和高脂肪饮食诱导的肝脏脂肪变性的发展。目标 3 将使用胃 X/A 样细胞中 ETV5 基因表达发生改变的小鼠来检查胃 X/A 样细胞中的 ETV5 是否会改变肝脏脂质代谢以及高脂肪饮食诱导的肝脂肪变性的发展。目标 4 将确定酰基生长素释放肽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 对肝脏脂质代谢的影响。我们将利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 NAFLD 的全新治疗方法，即针对胃部部位的治疗方法。