HEPATIC FLUXES IN PGC-1 ALPHA KO MICE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肥胖症的日益普遍正在推动相关代谢疾病的发病率激增，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）。脂质体内平衡的紊乱（继发于脂肪酸供过于求）在这些疾病的发病机制中起主要作用。然而，控制脂肪酸代谢的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（过氧化物酶体增殖物激活受体）辅激活因子1（PGC-1 α）是一种高度诱导的辅激活因子，通过转录激活这些代谢途径中的多个靶点，协调肝脏线粒体脂肪酸氧化、氧化磷酸化和肝异生的能力。PGC-1在肥胖和糖尿病等代谢疾病中在肌肉和肝脏中起着重要作用。在肌肉中，PGC-1表达在胰岛素抵抗中降低，这与脂肪和碳水化合物氧化之间的不适当转换一致。 肝脏脂肪酸稳态在基因转录水平上受核受体转录因子家族、过氧化物酶体增殖物激活受体（PPARs）及其共激活蛋白（PGC-1 α）的调节。PGC-1 α是一种高度诱导的辅激活因子，可调节控制多种能量代谢途径的转录因子，包括脂肪生成、线粒体氧化磷酸化、脂肪酸催化剂和甘油三酯合成和分泌。

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.