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。最近的研究表明，肥胖介导的代谢应激可诱导来自内质网（ER）的分子信号通路。一个主要的ER应激反应途径涉及JNK 1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的丧失。JNK 1也被炎症应激介质如TNF-α激活。非甾体抗炎药（NSAID）阿司匹林及其代谢产物水杨酸钠对细胞生理学具有深远的影响，并广泛用于治疗包括炎症和癌症在内的许多疾病。我们已经发现水杨酸盐通过应激激活的eIF 2 α激酶ER-驻留激酶PERK诱导翻译起始因子eIF 2 α亚基（eIF 2 α）的磷酸化，从而抑制EIF 2 α的表达。 蛋白质合成PERK作为应激ER的未折叠蛋白质反应的一部分被激活，导致蛋白质合成减少和ER应激缓解。然而，由水杨酸盐调节的ER应激途径可能是非常规的。我们发现水杨酸处理导致Caspase-12激活和CHOP（gadd 153）诱导，这两个事件已知伴随ER应激反应。相反，ER应激的良好表征介质IRE-1没有被激活。鉴于水杨酸调节炎症和内质网应激途径，这些途径与葡萄糖调节和癌症有关，我们建议测试水杨酸作用通过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JNK 1的活性。将检查JNK 1下游的事件，其指示胰岛素信号传导，例如IRS-1的抑制性和激活性磷酸化。此外，我们还将研究JNK 1上游的分子途径，以确定JNK 1的相对贡献。 与水杨酸盐抑制IKK β相比，水杨酸盐激活PERK。这些研究的主要目的是提高我们对水杨酸盐治疗是否可能在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方面具有治疗用途的理解。