Pilot: Regulation of Obesity and ER Stress by Salicylates

试点：水杨酸盐调节肥胖和内质网应激

• 批准号: 7007855
• 负责人: Bryan R. G. Williams
• 金额: $ 25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7007855
• 关键词: JUN kinase; cancer risk; endoplasmic reticulum; enzyme activity; enzyme induction /repression; genetically modified animals; insulin receptor; insulin sensitivity /resistance; laboratory mouse; obesity; phosphorylation; physiologic stressor; salicylate; serine threonine protein kinase; translation factor

Obesity is a risk factor for development of cancer. The molecular mechanisms that connect diet and weight gain to cancer have not been clearly elucidated. Recently, it has been shown that obesity-mediated metabolic stresses induce molecular signaling pathways that emanate from the endoplasmic reticulum (ER). A major ER stress responsive pathway involves activation of JNK1 leading to inhibitory serine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1, insulin resistance and loss of glucose regulation. JNK1 is also activated by mediators of inflammatory stress such as TNF-alpha. The non-steroidal anti-inflammatory drug (NSAID) aspirin and its metabolite, sodium salicylate, have profound effects on cell physiology and are widely used to treat a number of diseases including inflammation and cancer. We have found that salicylates induce phosphorylation of the a-subunit of translation initiation factor eIF2 (eIF2alpha) by the stress-activated eIF2alpha kinase ER-resident kinase PERK, resulting in inhibition of protein synthesis. PERK is activated as part of the unfolded protein response of a stressed ER, leading to reduced protein synthesis and ER stress relief. However, the ER stress pathway(s) regulated by salicylates may be unconventional. We found that salicylate treatment led to Caspase-12 activation and CHOP(gadd153) induction, two events known to accompany ER stress responses. In contrast, the well-characterized mediator of ER stress, IRE-1, was not activated. Given that salicylates regulate both inflammatory and ER stress pathways and that these pathways have been implicated in glucose regulation and cancer, we propose to test the hypothesis that salicylate action modulates insulin action via a PERK-dependent pathway. Accordingly, we will determine whether salicylates affect the activity of JNK1 in wild type mice and murine models of obesity. Events downstream of JNK1 that indicate insulin signaling such as inhibitory and activating phosphorylation of IRS-1 will be examined. In addition, we will investigate the molecular pathways upstream of JNK1 to determine the relative contribution of salicylate activation of PERK as compared to salicylate inhibition of IKKbeta. The broad objective of these studies is to improve our understanding of whether salicylate treatment might be of therapeutic use in restoring insulin sensitivity and appropriate glucose regulation to ultimately prevent obesity and its health consequences.

肥胖是癌症发生的危险因素。将饮食和体重增加与癌症联系起来的分子机制尚未明确阐明。最近，研究表明，肥胖介导的代谢应激会诱导内质网（ER）发出的分子信号传导途径。主要的 ER 应激反应途径涉及 JNK1 的激活，导致胰岛素受体和胰岛素受体底物 (IRS)-1 的抑制性丝氨酸磷酸化、胰岛素抵抗和葡萄糖调节丧失。 JNK1 也会被 TNF-α 等炎症应激介质激活。非甾体抗炎药（NSAID）阿司匹林及其代谢物水杨酸钠对细胞生理学具有深远影响，广泛用于治疗包括炎症和癌症在内的多种疾病。我们发现水杨酸盐通过应激激活的 eIF2α 激酶 ER 驻留激酶 PERK 诱导翻译起始因子 eIF2 (eIF2α) 的 a 亚基磷酸化，从而抑制 蛋白质合成。 PERK 作为应激内质网未折叠蛋白反应的一部分被激活，导致蛋白合成减少和内质网应激缓解。然而，水杨酸盐调节的内质网应激途径可能是非常规的。我们发现水杨酸盐治疗导致 Caspase-12 激活和 CHOP(gadd153) 诱导，这两个事件已知伴随 ER 应激反应。相比之下，内质网应激的众所周知的调节因子 IRE-1 并未被激活。鉴于水杨酸盐调节炎症和内质网应激途径，并且这些途径与葡萄糖调节和癌症有关，我们建议检验水杨酸盐作用通过 PERK 依赖性途径调节胰岛素作用的假设。因此，我们将确定水杨酸盐是否影响野生型小鼠和肥胖小鼠模型中 JNK1 的活性。将检查 JNK1 下游指示胰岛素信号传导的事件，例如 IRS-1 的抑制和激活磷酸化。此外，我们将研究 JNK1 上游的分子途径，以确定 水杨酸对 PERK 的激活与水杨酸对 IKKbeta 的抑制进行比较。这些研究的广泛目标是提高我们对水杨酸盐治疗是否可以用于恢复胰岛素敏感性和适当的葡萄糖调节以最终预防肥胖及其健康后果的治疗用途的理解。