Sir2 Regulates AMPK and Lipid Metabolism in Diabetes

Sir2 调节糖尿病中的 AMPK 和脂质代谢

• 批准号: 8305735
• 负责人: MENGWEI ZANG
• 金额: $ 33.13万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305735
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Acetyl-CoA Carboxylase; Aging; Antidiabetic Drugs; Area; Atherosclerosis; Attenuated; Binding Proteins; Blood Vessels; Caloric Restriction; Cardiovascular Pathology; Chronic; Cultured Cells; Data; Deacetylase; Deacetylation; Dependence; Development; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Dose; Drug usage; Dyslipidemias; Fatty acid glycerol esters; Fruit; Glucose; Health; Hepatic; Hepatocyte; Human; Hyperglycemia; Hyperlipidemia; In Vitro; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Link; Lipids; Liver; Longevity; Low Density Lipoprotein Receptor; Mediating; Metabolic; Metabolic Diseases; Metabolism; Metformin; Methods; Modeling; Molecular; Mus; Obesity; Orthologous Gene; Pathogenesis; Pathway interactions; Patients; Publishing; Regulation; Regulatory Element; Research; Resveratrol; Role; S17834; STK11 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Sterols; Testing; Therapeutic; Therapeutic Effect; Time; Up-Regulation; Work; age related; atherogenesis; diabetic; dietary restriction; feeding; gain of function; improved; in vivo; in vivo Model; innovation; insight; lipid metabolism; loss of function; mortality; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; polyphenol; prevent; protective effect; protein function; red wine; response; sensor; trend; type I and type II diabetes; type I diabetic; upstream kinase

DESCRIPTION (provided by applicant): Obesity, insulin resistance, diabetes and hyperlipidemia are leading causes of cardiovascular pathology and mortality. SIRT1, a mammalian ortholog of silent information regulator 2 (Sir2), is an NAD-dependent deacetylase mediates the effects of caloric restriction to expend lifespan. The energy sensor AMP-activated protein kinase (AMPK) and its upstream kinase, LKB1, have been implicated in the therapeutic effect of metformin, an anti-diabetic drug used worldwide. My recent studies and others indicate that both master metabolic regulators, SIRT1 and AMP-activated protein kinase (AMPK), are activated by polyphenols including resveratrol present in red wine. However, If and how SIRT1 is linked to AMPK signaling, lipid metabolism and atherosclerosis remains elusive. I have established in vitro hepatocyte models and in vivo models of type 1 and type 2 diabetic LDL receptor-deficient (LDLR-/-) mice to provide new evidence that 1) polyphenols strongly prevent the inhibition of AMPK, and upregulation of acetyl-CoA carboxylase (ACC) and regulatory element binding protein (SREBP), two key downstream effectors of AMPK, and reduce hepatic lipid accumulation, thereby attenuating diabetic hyperlipidemia and atherosclerosis; 2) the stimulation of AMPK and lipid-lowering action of polyphenols are abrogated by inhibition of SIRT1 or AMPK in vitro; 3) hepatocyte overexpression of SIRT1 stimulates AMPK, downregulates SREBP function and lowers lipids in vitro and in vivo. The CENTRAL HYPOTHESIS of this proposal is that SIRT1 activation by polyphenols functions as a novel upstream regulator of LKB1/AMPK signaling to modulate hepatocyte lipid metabolism and has potential therapeutic implications in the hyperlipidemia and atherosclerosis caused by diabetes. In my three SPECIFIC AIMS, I will test the hypothesis that 1) SIRT1 activation by polyphenols regulates AMPK activity via a mechanism underlying deacetylation of LKB1; 2) polyphenols and SIRT1, via LKB1/AMPK signaling, control ACC and SREBP and their lipid metabolic consequences in hepatocytes in vitro; and 3) the in vivo integrated function of SIRT1 and LKB1/AMPK has been implicated in the development of hyperlipidemia and atherosclerosis in diabetes and in the protective effect of polyphenols against metabolic disease. Innovative aspects of the application include: new insights into the molecular mechanism for the function of SIRT1 as a novel upstream signaling of LKB1/AMPK pathway to control lipid metabolism, and the new concept that SIRT1, via LKB1/AMPK/SREBP signaling, regulates lipid metabolism and atherosclerosis in diabetes. Thus, the proposed studies will emphasize targeting SIRT1/LKB1/AMPK as a new therapeutic avenue to benefit hyperlipidemia and atherosclerosis in diabetes and age-related metabolic disorder. PUBLIC HEALTH RELEVANCE: Although caloric restriction (CR) extends the lifespan and delays the onset of age-related diseases such as diabetes, current trends in unlikelihood that patient with obesity and diabetes would be willing or able to maintain a calorie-restricted diet. This situation gives rise to an important question: "what agents can mimic the beneficial effect of CR?". Ongoing work will employ both in vitro hepatocyte model and in vivo type 2 diabetic mouse models to determine how polyphenols including resveratrol, which is present in red wine and polyphenol-rich fruits, and mimics the beneficial effect of CR, protects against hyperlipidemia and accelerated atherosclerosis in diabetes through activation of the longevity factor SIRT1 and the energy sensor AMPK signaling. Activation of SIRT1/AMPK signaling will provide new therapeutic targets for intervention of diabetes and its vascular complications.

描述（由申请人提供）：肥胖，胰岛素抵抗，糖尿病和高脂血症是心血管病理和死亡率的主要原因。 SIRT1是一种沉默信息调节剂2（SIR2）的哺乳动物直系同源物，是一种NAD依赖性脱乙酰基酶，介导了热量限制对支出寿命的影响。能量传感器AMP激活的蛋白激酶（AMPK）及其上游激酶LKB1与二甲双胍的治疗作用有关，二甲双胍是全球使用的一种抗糖尿病药物。我最近的研究和其他研究表明，主要的代谢调节剂SIRT1和AMP激活的蛋白激酶（AMPK）都被包括红酒中存在的白藜芦醇在内的多酚激活。但是，如果以及如何与AMPK信号传导相关，脂质代谢和动脉粥样硬化仍然难以捉摸。 I have established in vitro hepatocyte models and in vivo models of type 1 and type 2 diabetic LDL receptor-deficient (LDLR-/-) mice to provide new evidence that 1) polyphenols strongly prevent the inhibition of AMPK, and upregulation of acetyl-CoA carboxylase (ACC) and regulatory element binding protein (SREBP), two key downstream effectors of AMPK并减少肝脂质积累，从而减轻糖尿病高脂血症和动脉粥样硬化； 2）通过抑制SIRT1或AMPK的体外，可以消除多酚的AMPK和降脂作用； 3）SIRT1的肝细胞过表达刺激AMPK，下调SREBP功能，并在体外和体内降低脂质。该提议的中心假设是，多酚的SIRT1激活是LKB1/AMPK信号传导的新型上游调节剂，以调节肝细胞脂质代谢，并在高脂血症和动脉粥样硬化中具有潜在的治疗意义。在我的三个特定目标中，我将测试以下假设：1）多酚通过LKB1的脱乙酰基化的机制调节AMPK活性； 2）通过LKB1/AMPK信号传导，控制ACC和SREBP以及其在体外肝细胞中的脂质代谢后果，多酚和SIRT1。 3）SIRT1和LKB1/AMPK的体内整合功能与糖尿病中的高脂血症和动脉粥样硬化的发展有关，以及多酚对代谢疾病的保护作用。该应用程序的创新方面包括：对SIRT1功能的分子机制的新见解，作为控制脂质代谢的LKB1/AMPK途径的新型上游信号传导，以及通过LKB1/AMPK/SREBP信号传导SIRT1，SIRT1通过LKB1/AMPK/SREBP信号来调节Lipid Signalliss，可调节Lipid Signersliss和Atherabolismiss和Atheremossiss。因此，拟议的研究将强调靶向SIRT1/LKB1/AMPK作为一种新的治疗途径，以使糖尿病和与年龄有关的代谢疾病中的高脂血症和动脉粥样硬化。公共卫生相关性：尽管热量限制（CR）延长了寿命，并延迟了与年龄有关的疾病（例如糖尿病）的发作，但肥胖和糖尿病患者愿意或能够维持卡路里限制饮食的不可能的当前趋势。这种情况引起了一个重要的问题：“哪些代理可以模仿CR的有益效果？”。正在进行的工作将采用体外肝细胞模型和体内2型糖尿病小鼠模型，以确定包括红酒和富含多酚的水果中存在的多酚包括如何使用CR的有益效果，从而可以通过糖尿病的糖尿病效应来保护CR的有益效果，并通过激活型糖尿病来保护糖尿病，并在糖尿病上使用激活效率。 SIRT1/AMPK信号的激活将为糖尿病及其血管并发症的干预提供新的治疗靶标。

项目成果

Fibroblast growth factor 21 improves hepatic insulin sensitivity by inhibiting mammalian target of rapamycin complex 1 in mice.

成纤维细胞生长因子 21 通过抑制小鼠雷帕霉素复合物 1 的哺乳动物靶点提高肝脏胰岛素敏感性

• DOI: 10.1002/hep.28523
• 发表时间: 2016-08
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Gong Q;Hu Z;Zhang F;Cui A;Chen X;Jiang H;Gao J;Chen X;Han Y;Liang Q;Ye D;Shi L;Chin YE;Wang Y;Xiao H;Guo F;Liu Y;Zang M;Xu A;Li Y
• 通讯作者: Li Y