LIPIN 1 IN THE REGULATION OF HEPATIC LIPID METABOLISM

描述（由申请人提供）：肥胖的流行正在推动相关代谢疾病（包括非酒精性脂肪性肝病（NAFLD））的发病率激增。事实上，肥胖与肝脂肪变性、炎症和功能障碍的发展密切相关。据信，在肥胖受试者中，脂肪酸的供应远远超过脂肪酸氧化或脂蛋白分泌的肝脏能力。因此，更全面地了解控制肝脏脂质稳态的途径具有重要的生理和临床意义。已知脂肪酸催化剂的能力在基因转录水平上由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？）控制。PGC-1？？是一种高度诱导的辅激活因子，转录调节多种能量代谢途径，包括线粒体氧化磷酸化和脂肪酸氧化。最近，我们制造了PGC-1基因缺陷的小鼠。(PGC-1？？-/-小鼠）。虽然PGC-1？-/-小鼠外观正常，PGC-1？-/-小鼠表现出脂肪酸氧化和禁食诱导的脂肪变性的速率降低。基因表达谱分析表明，编码脂蛋白1的基因在野生型小鼠的肝脏中具有明显的禁食诱导作用，但在PGC-1？？-/-老鼠。脂蛋白1基因突变导致fld小鼠脂肪代谢障碍和脂肪肝，fld小鼠的肝细胞表现出围产期脂肪变性和棕榈酸氧化速率降低。我们的初步数据表明，lipin 1增强了活性的过氧化物酶体增殖物激活受体？？/PGC-1？？系统，并增加参与线粒体脂肪酸氧化的基因的表达。基于我们的初步数据，我们假设lipin 1通过参与肝线粒体脂肪酸代谢的基因的转录调节在控制脂质稳态中起重要作用。此外，我们假设脂蛋白1介导的许多这些影响，通过与PGC-1？？和它的转录因子伴侣。该提议旨在[1]表征lipin 1和PGC-1之间的功能相互作用，[2]使用互补的功能获得和功能丧失方法阐明lipin 1对肝脂肪酸代谢的转录作用，[3]并评价组成性lipin 1激活对小鼠模型中NAFLD发展的影响。肥胖症的日益普遍正在推动相关代谢疾病的发病率激增，包括非酒精性脂肪性肝病（NAFLD）。我们认为，了解一种名为lipin 1的蛋白质如何影响脂肪酸代谢，对于开发治疗NAFLD患者的新疗法可能很重要。

DESCRIPTION (provided by applicant): The prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including non-alcoholic fatty liver disease (NAFLD). Indeed, obesity is tightly linked to the development of hepatic steatosis, inflammation, and dysfunction. It is believed that, in obese subjects, the supply of fatty acids far exceeds the hepatic capacity for fatty acid oxidation or secretion in lipoproteins. Therefore, a more complete understanding of the pathways that control hepatic lipid homeostasis has important physiological and clinical implications. The capacity for fatty acid catabolism is known to be controlled 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-1?). PGC-1?? is a highly-inducible coactivator that transcriptionally regulates multiple energy metabolic pathways including mitochondrial oxidative phosphorylation and fatty acid oxidation. Recently, we generated mice deficient for PGC-1?? (PGC- 1?? -/- mice). Although PGC-1?? -/- mice appeared outwardly normal, hepatocytes from PGC-1?? -/- mice exhibited diminished rates of fatty acid oxidation and fasting-induced steatosis. Gene expression profiling identified the gene encoding lipin 1 as markedly fasting-induced in the liver of wild-type, but not PGC-1?? -/- mice. Lipin 1 gene mutations lead to lipodystrophy and fatty liver in fld mice and hepatocytes from fld mice exhibit perinatal steatosis and diminished rates of palmitate oxidation. Our preliminary data indicate that lipin 1 augments the activity of the PPAR?? /PGC-1?? system and increases the expression of genes involved in mitochondrial fatty acid oxidation. Based on our preliminary data, we hypothesize that lipin 1 plays an important role in controlling lipid homeostasis via transcriptional regulation of genes involved in hepatic mitochondrial fatty acid metabolism. Furthermore, we postulate that lipin 1 mediates many of these effects via interactions with PGC-1?? and its partner transcription factors. This proposal is designed to [1] characterize the functional interaction between lipin 1 and PGC-1??, [2] elucidate the transcriptional effects of lipin 1 on hepatic fatty acid metabolism using complimentary gain-of-function and loss-of-function approaches, and [3] to evaluate the effects of constitutive lipin 1 activation on the development of NAFLD in mouse models. The increasing prevalence of obesity is driving a surge in the incidence of associated metabolic diseases including non-alcoholic fatty liver disease (NAFLD). We believe that understanding how a protein called lipin 1 impacts fatty acid metabolism may be important for the development of new therapies to treat patients with NAFLD.