HEPATIC FLUXES IN PGC-1 ALPHA KO MICE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 肥胖的日益流行导致相关代谢性疾病的发病率激增，包括胰岛素抵抗、2型糖尿病、高脂血症和非酒精性脂肪性肝病(NAFLD)。脂类平衡的紊乱(继发于脂肪酸供应过剩)在这些疾病的发病机制中起主要作用。然而，控制脂肪酸代谢关键成分的机制仍有待发现。过氧化物酶体增殖物激活受体(PPAR)共激活剂1(PGC-1α)是一种高度可诱导的共激活剂，通过转录激活这些代谢途径中的多个靶点来协调肝脏线粒体脂肪酸氧化、氧化磷酸化和糖异生的能力。在肥胖和糖尿病等代谢性疾病中，PGC-1在肌肉和肝脏中都扮演着重要的角色。在肌肉中，PGC-1的表达在胰岛素抵抗时减少，这与脂肪和碳水化合物氧化之间的不适当切换一致。肝脏脂肪酸稳态受一系列核受体转录因子、过氧化物酶体增殖物激活受体(PPAR)及其辅助激活蛋白(PGC-1α)在基因转录水平上的调节。PGC-1α是一种高度可诱导的共激活因子，可调控多种能量代谢途径的转录因子，包括糖异生、线粒体氧化磷酸化、脂肪酸分解代谢以及甘油三酯的合成和分泌。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The increasing prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and non-alcoholic fatty liver disease (NAFLD). Perturbations in lipid homeostasis (secondary to fatty acid oversupply) play a primary role in the pathogenesis of each of these diseases. However, the mechanisms controlling key constituents of fatty acid metabolism remain to be discovered. The peroxisome proliferator-activated receptor (PPAR) coactivator 1 (PGC-1alpha) is a highly inducible coactivator that coordinates the capacity for hepatic mitochondrial fatty acid oxidation, oxidative phosphorylation, and gluconeogenesis via transcriptional activation of multiple targets in these metabolic pathways. PGC-1 plays an important role in both muscle and liver during metabolic maladies such as obesity and diabetes. In muscle, PGC-1 expression is decreased in insulin resistance consistent with inappropriate switching between fat and carbohydrate oxidation. Hepatic fatty acid homeostasis is modulated at the level of gene transcription by a family of nuclear receptor transcription factors, the peroxisome proliferator-activated receptors (PPARs) and their coactivator protein (PGC-1alpha). PGC-1alpha is a highly-inducible coactivator that regulates transcription factors controlling multiple energy metabolic pathways including gluconeogenesis, mitochondrial oxidative phosphorylation, fatty acid catabolism, and triglyceride synthesis and secretion.