Regulation of glucose homeostasis by C/EBPB

C/EBPB 对葡萄糖稳态的调节

• 批准号: 7883205
• 负责人: JACOB E FRIEDMAN
• 金额: $ 29.03万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883205
• 关键词: ADD-1 protein; Acute; Address; Adenoviruses; Adolescent; Adult; Affect; Animals; Appetite Regulation; Biological; Biological Models; Brain; CCAAT-Enhancer-Binding Proteins; Cell Culture Techniques; Cell Line; Cells; Child; Cirrhosis; Clinical; Data; Deposition; Desire for food; Development; Diabetes Mellitus; Diet; Disease; Distal; Dominant-Negative Mutation; Eating; Energy Intake; Energy Metabolism; Epidemic; Fatty Liver; Fibrosis; Functional disorder; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Gluconeogenesis; Glucose; Goals; Hepatic; Hyperglycemia; Hyperlipidemia; Hyperphagia; Hypothalamic structure; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Laboratories; Leptin; Lip structure; Lipids; Liver; Liver Function Tests; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Nuclear; Obesity; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phosphoenolpyruvate Carboxylase; Play; Population; Preparation; Protein Isoforms; Protocols documentation; Regulation; Regulator Genes; Research; Research Personnel; Resistance; Role; Signal Transduction; Staining method; Stains; Steatohepatitis; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Triglyceride Metabolism; Triglycerides; United States; adipocyte differentiation; base; blood glucose regulation; experience; fasting glucose; glucose metabolism; immunocytochemistry; in vivo; knockout animal; leptin receptor; lipid biosynthesis; liver biopsy; metabolic abnormality assessment; non-alcoholic fatty liver; nonalcoholic steatohepatitis; prevent; programs; response; transcription factor

DESCRIPTION (provided by applicant): The United States is experiencing an epidemic of obesity-driven metabolic disorders which is even greater in juvenile populations. The metabolic abnormalities accompanying obesity frequently involve inflammation, hyperlipidemia, and hyperglycemia, however the transcriptional mechanisms underlying these abnormalities remain poorly understood. Recent results from this laboratory in mice lacking CCAAT/Enhancer Binding Protein b have revealed a remarkable array of metabolic regulatory functions for C/EBPb, including significant effects on energy intake, gluconeogenesis, and triglyceride metabolism. The proposed research is based on the hypothesis that C/EBPb is required for regulating gluconeogenic and lipogenic responses in the liver and mediating aspects of leptin-mediated gene transcription yet to be described. The long-term goals of this proposal are to further characterize the metabolic effects of C/EBPb in liver and brain, to identify target genes and the regulatory mechanisms involved, and to understand the potential role of C/EBPb in development of fatty liver. In Specific aim 1 we will generate tissue-specific knockout mice to determine the role of C/EBPb in liver and brain on resistance to obesity. In Specific Aim 2, the biological consequences of the truncated isoforms of C/EBPb on triglyceride synthesis and metabolism will be examined in livers from transgenic and cell culture models. We will also examine whether PPARa is required for C/EBPb knockdown to inhibit hepatic lipogenesis using substrate metabolism, gene array, and PPAR knockout cell lines. In Specific Aim 3 we will determine the metabolic consequences of over-expressing the activating (LAP) and liver inhibiting (LIP) form of C/EBPb on lipogenesis and gluconeogenesis in-vivo. Lastly, in Specific Aim 4 we will determine whether C/EBPb plays a role in the liver of obese children with fatty liver disease. Our studies will quantify lipid staining and address whether C/EBPb and other transcription factors involved in lipogenesis are over-expressed in the liver from obese subjects with NAFLD and NASH and their relationship to the lipid positive cells. The studies described in this proposal will have important clinical implications for understanding the pathways that control liver gluconeogenesis and lipogenesis and could open up new avenues for understanding mechanisms contributing to obesity, diabetes, and fatty liver disease.

描述（由申请人提供）：美国正在经历由肥胖引起的代谢紊乱的流行，这种情况在青少年群体中更为严重。肥胖伴随的代谢异常经常涉及炎症、高脂血症和高血糖，然而这些异常背后的转录机制仍然知之甚少。该实验室最近在缺乏 CCAAT/增强子结合蛋白 b 的小鼠中进行的研究结果揭示了 C/EBPb 的一系列显着的代谢调节功能，包括对能量摄入、糖异生和甘油三酯代谢的显着影响。拟议的研究基于这样的假设：C/EBPb 是调节肝脏中糖异生和脂肪生成反应所必需的，并且介导瘦素介导的基因转录方面尚未描述。该提案的长期目标是进一步表征C/EBPb在肝脏和大脑中的代谢作用，识别靶基因和所涉及的调节机制，并了解C/EBPb在脂肪肝发展中的潜在作用。在具体目标 1 中，我们将生成组织特异性敲除小鼠，以确定肝脏和大脑中 C/EBPb 对抵抗肥胖的作用。在具体目标 2 中，将通过转基因和细胞培养模型在肝脏中检查 C/EBPb 截短亚型对甘油三酯合成和代谢的生物学影响。我们还将使用底物代谢、基因阵列和 PPAR 敲除细胞系来检查 PPARa 是否是 C/EBPb 敲低所必需的，以抑制肝脏脂肪生成。在具体目标 3 中，我们将确定过度表达 C/EBPb 的激活 (LAP) 和肝抑制 (LIP) 形式对体内脂肪生成和糖异生的代谢后果。最后，在具体目标 4 中，我们将确定 C/EBPb 是否在患有脂肪肝疾病的肥胖儿童的肝脏中发挥作用。我们的研究将量化脂质染色，并探讨 C/EBPb 和其他参与脂肪生成的转录因子是否在患有 NAFLD 和 NASH 的肥胖受试者的肝脏中过度表达，以及它们与脂质阳性细胞的关系。该提案中描述的研究将对了解控制肝脏糖异生和脂肪生成的途径具有重要的临床意义，并可能为了解导致肥胖、糖尿病和脂肪肝疾病的机制开辟新途径。

项目成果

Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation.

脂肪肝与 SIRT3 活性降低和线粒体蛋白过度乙酰化有关。

• 发表时间: 2011-02-01
• 作者: Kendrick, Agnieszka A;Choudhury, Mahua;Rahman, Shaikh M;McCurdy, Carrie E;Friederich, Marisa;Van Hove, Johan L K;Watson, Peter A;Birdsey, Nicholas;Bao, Jianjun;Gius, David;Sack, Michael N;Jing, Enxuan;Kahn, C Ronald;Friedman, Jacob E;Jonsche
• 通讯作者: Jonsche

CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis.

小鼠中CCAAT/增强结合蛋白β缺失可减轻饮食诱导的非酒精性脂肪性肝炎中的炎症、内质网应激和脂质积累。

• 发表时间: 2007-05
• 作者: Rahman, Shaikh Mizanoor;Schroeder;Janssen, Rachel C;Jiang, Hua;Qadri, Ishtiaq;Maclean, Kenneth N;Friedman, Jacob E
• 通讯作者: Friedman, Jacob E

De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific.

骨髓谱系通过间充质中间体从头生成白色脂肪细胞具有年龄、脂肪库和性别特异性。

• 发表时间: 2010-08-17
• 影响因子: 11.1
• 作者: Majka, Susan M;Fox, Keith E;Psilas, John C;Helm, Karen M;Childs, Christine R;Acosta, Alistaire S;Janssen, Rachel C;Friedman, Jacob E;Woessner, Brian T;Shade, Theodore R;Varella;Klemm, Dwight J
• 通讯作者: Klemm, Dwight J

Fenofibrate and PBA prevent fatty acid-induced loss of adiponectin receptor and pAMPK in human hepatoma cells and in hepatitis C virus-induced steatosis.

非诺贝特和 PBA 可防止脂肪酸诱导的人肝癌细胞中脂联素受体和 pAMPK 以及丙型肝炎病毒诱导的脂肪变性的丧失。

• 发表时间: 2009-11
• 影响因子: 6.5
• 作者: Rahman, Shaikh Mizanoor;Qadri, Ishtiaq;Janssen, Rachel C;Friedman, Jacob E
• 通讯作者: Friedman, Jacob E

C/EBPβ is AMP kinase sensitive and up-regulates PEPCK in response to ER stress in hepatoma cells.

C/EBPβ 是 AMP 激酶敏感的，并上调 PEPCK 以响应肝癌细胞中的 ER 应激。

• 发表时间: 2011-01-01
• 影响因子: 4.1
• 作者: Choudhury, Mahua;Qadri, Ishtiaq;Rahman, Shaikh Mizanoor;Schroeder;Janssen, Rachel C;Friedman, Jacob E
• 通讯作者: Friedman, Jacob E