通过核激素受体PPAR-gamma,CREB控制肝脏脂质代谢
Stephan Herzig1, Susan Hedrick, Ianessa Morantte
1Peptide Biology Laboratories Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037-1002, USA.
Nature
|November 14, 2003
概括
禁食通过激活CREB来抑制脂肪合成,CREB通过HES-1抑制PPAR-玛. 这种机制解释了在禁食期间肝脏脂肪的调节,并建议治疗胰岛素敏感性的点.
科学领域:
- 代谢调节 代谢调节 代谢调节
- 分子内分泌学分子内分泌学
- 激素信号传递 激素信号传递
背景情况:
- 禁食诱导肝脏的葡萄糖输出和脂质分解通过荷尔蒙线索.
- 对cAMP反应的元素结合蛋白 (CREB) 激活了葡萄糖生成和脂肪酸氧化通路.
- 禁食期间抑制肝脏脂质生路径的机制在很大程度上是未知的.
研究的目的:
- 阐明禁食抑制肝脂发生的分子机制.
- 研究CREB及其下游目标在禁食期间调节脂质代谢中的作用.
主要方法:
- 利用缺乏CREB的小鼠研究肝脏表型.
- 分析了核激素受体 (例如PPAR-gamma) 和转录抑制剂 (例如HES-1) 的基因表达.
- 研究了HES-1在禁食诱导的脂质代谢中的体内作用.
主要成果:
- 缺乏CREB的小鼠表现出脂肪肝表型,PPAR-gamma表达升高.
- 发现CREB通过刺激HES-1在禁食期间抑制肝脏PPAR-gamma表达.
- 在体内,HES-1 作为禁食脂质代谢的调解者.
结论:
- 在禁食期间,CREB协调PGC-1的诱导和PPAR-gamma的抑制.
- 这为胰岛素和逆调节激素之间的相互作用提供了分子基础.
- CREB 抗体可能是改善肝脏胰岛素敏感性的治疗策略.
相关概念视频
Cell Specific Gene Expression
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
Co-activators and Co-repressors
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
Regulation of Nuclear Protein Sorting
Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
Co-activators and Co-repressors
Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
Transducer Mechanism: Nuclear Receptors
Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
Lipid Catabolism
Triglycerides serve as crucial long-term energy storage molecules in microorganisms, providing a dense source of metabolic energy. Their breakdown is mediated by lipases, which hydrolyze triglycerides into glycerol and free fatty acids. Each of these components follows distinct metabolic pathways, ultimately contributing to ATP synthesis and cellular energy homeostasis.Glycerol MetabolismGlycerol, released from triglyceride hydrolysis, is phosphorylated by glycerol kinase to form...


