p38 MAPK regulation of hepatic gluconeogenesis and lipogenesis

p38 MAPK 对肝脏糖异生和脂肪生成的调节

• 批准号: 7322193
• 负责人: Wenhong Cao
• 金额: $ 31.08万
• 依托单位: THE HAMNER INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322193
• 关键词: Adenovirus Vector; Amplifiers; Animals; Binding Proteins; Blood; Blood Glucose; C57BL/6 Mouse; CREB1 gene; Cell Line; Complex; Cyclic AMP Response Element; Diabetes Mellitus; Disease; Dyslipidemias; Fasting; Fatty Liver; Figs - dietary; Genes; Genetic Transcription; Glucagon; Gluconeogenesis; Glucose; Goals; Hepatic; Hepatocyte; Hormonal; Hyperglycemia; Lead; Learning; Lipids; Liver; MAP Kinase Gene; MAPK11 gene; MAPK14 gene; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; PPAR gamma; Peroxisome Proliferator-Activated Receptors; Phosphoenolpyruvate Carboxylase; Plasma; Prevention; Process; Rate; Recombinants; Regulation; Regulatory Element; Role; Sterols; Techniques; Testing; Transcription Coactivator; base; diabetic; glucose-6-phosphatase; hepatic gluconeogenesis; hepatoma cell; human MAPK14 protein; in vivo; insight; lipid biosynthesis; lipid disorder; mitogen-activated protein kinase p38; mouse model; promoter

DESCRIPTION (provided by applicant): Disorders of hepatic gluconeogenesis and lipogenesis may lead to metabolic problems such as diabetes, dyslipidemia, and fatty liver. Our long-term goal is to investigate the mechanisms by which p38 regulates hepatic gluconeogenesis and lipogenesis, and provide new targets for the prevention and treatment of metabolic disorders such as diabetes and dyslipidemia. The specific hypothesis is that activation of p38 stimulates gluconeogenesis, while simultaneously inhibiting lipogenesis; the stimulatory role of p38 is accomplished by promoting the function of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1 alpha), while the inhibitory role of p38 is mediated by suppressing expression of the PPARgamma coactivator-1 beta (PGC-1 beta) gene. This hypothesis is based on our observations that 1) p38 is activated in liver by fasting and in isolated hepatocytes by glucagon; 2) p38 stimulates expression of the PGC-1 alpha gene, but inhibits expression of the PGC-1 beta gene; 3) Inhibition of p38 reduces expression of key gluconeogenic genes, while increasing expression of key lipogenic genes; and 4) The blockade of p38 leads to decreased levels of fasting plasma glucose and increased lipid levels in blood and liver. Four specific aims are proposed to test the hypothesis. Aim 1: To characterize the key components by which p38 regulates transcription of the PGC-1 alpha gene in hepatic gluconeogenesis. Aim 2: To determine how p38 inhibits transcription of the PGC-1 beta gene in hepatic lipogenesis. Aim 3: To delineate the transcriptional components required for p38 regulation of the central lipogenic gene, sterol regulatory element binding protein-1c (SREBP-1c). Aim 4: To test the hypothesis that the blockade of p38 can reduce blood glucose levels in diabetic animals. Methods: Hepa-1c1c7 and FAO hepatoma cell lines, primary hepatocytes, and normal and diabetic C57BL/6 mouse models will be used in this study. A variety of molecular approaches will also be used. Significance: This study will provide new insight into mechanisms by which hepatic gluconeogenesis and lipogenesis are regulated. Completion of this study may provide new targets for the prevention and treatment of diabetes and lipid disorders.

描述（由申请人提供）：肝糖异生和脂肪生成的疾病可能导致代谢问题，例如糖尿病，血脂异常和脂肪肝肝脏。我们的长期目标是研究p38调节肝糖异生和脂肪生成的机制，并为预防和治疗代谢性疾病（例如糖尿病和血脂异常）提供了新的靶标。具体假设是，p38的激活刺激糖异生，同时抑制脂肪生成。 p38的刺激作用是通过促进过氧化物酶体增殖物激活的受体伽马（PPARGAMMA）共激活剂-1α（PGC-1 Alpha）的功能来实现的，而p38的抑制作用是通过抑制PPARGAMMA COCTIVATOR-1 BETA-1 BETA（PGC-1 BETA）Genee介导的p38抑制作用。该假设是基于我们的观察结果，即1）p38是通过禁食在肝脏中激活的，胰高血糖素在肝脏中被激活； 2）p38刺激PGC-1α基因的表达，但抑制了PGC-1β基因的表达； 3）抑制p38可降低关键糖原性基因的表达，同时增加关键脂肪生成基因的表达； 4）p38的封锁导致空腹血浆葡萄糖的水平降低，血液和肝脏中脂质水平升高。提出了四个特定目标来检验假设。目的1：表征p38在肝糖异生中调节PGC-1α基因转录的关键成分。 AIM 2：确定p38如何抑制肝脂肪生成中PGC-1β基因的转录。 AIM 3：描绘p38调控中心脂肪生成基因的转录成分，固醇调节元素结合蛋白1C（SREBP-1C）。目的4：测试以下假设：p38的封锁可以降低糖尿病动物中的血糖水平。方法：本研究将使用HEPA-1C1C7和FAO肝癌细胞系，原发性肝细胞以及正常和糖尿病C57BL/6小鼠模型。还将使用各种分子方法。意义：这项研究将提供有关调节肝糖异生和脂肪形成的机制的新见解。这项研究的完成可能为预防和治疗糖尿病和脂质疾病提供新的目标。