Fatty Acid Regulation of the Acute Inflammatory Response

描述（由申请人提供）：本申请的总体目标是：1)帮助申请人获得研究技能，以促进其发展为独立研究者，2)检查肝脏在脂质介导的炎症中的作用。非酒精性脂肪性肝病（NAFLD）是一种新兴的肥胖相关疾病，可增加脂肪性肝炎和隐源性肝硬化的风险。血清和肝脏脂质升高是NAFLD的一个特征，并与该疾病的局部和全身性炎症有关。CREBh是一种最近发现的肝脏特异性内质网定位转录因子，它在蛋白水解裂解后易位到细胞核，是急性期反应物c反应蛋白和血清淀粉样蛋白p组分转录所必需的。我们最近已经证明，长链脂肪酸增加CREBh基因和蛋白质的表达，前者通过依赖于完整蛋白酶体的转录机制，独立于细胞代谢。因此，CREBh可能是血脂升高、炎症和代谢性疾病之间的重要联系。然而，脂肪酸激活CREBh的具体机制尚不清楚。鉴于CREBh诱导不需要脂肪酸代谢，脂肪酸的特定靶标可能包括一个独立于细胞代谢的因子。toll样受体（TLR），特别是TLR4，在先天免疫中起着至关重要的作用，并可被脂多糖（LPS）的脂质成分激活。最近的数据表明，脂肪酸诱导的脂肪细胞、骨骼肌和内皮细胞的胰岛素抵抗和炎症在抑制TLR4信号后被阻止。在肝脏中，几种细胞类型表达TLR4和/或TLR2，包括Kupffer细胞、星状细胞和肝细胞。最近的数据表明，TLR4信号在肝脂肪变性和肝损伤中起关键作用，我们实验室的初步数据表明，通过LPS激活TLR4可诱导H4IIE肝细胞中CREBh基因的表达。因此，我们假设TLR4介导脂肪酸对CREBh的调节。当前提案中的实验旨在直接验证这一假设。

DESCRIPTION (provided by applicant): The global objectives of this application are: 1) to assist the applicant in the acquisition of research skills that will facilitate his development into an independent investigator, and 2) to examine the role of the liver in lipid-mediated inflammation. Non-alcoholic fatty liver disease (NAFLD) is a burgeoning obesity-related disorder that increases the risk of steatohepatitis and cryptogenic cirrhosis. Elevated serum and hepatic lipids are a characteristic feature of NAFLD and have been implicated in both the local and systemic inflammation present in this disease. CREBh is a recently identified, liver-specific, endoplasmic reticulum- localized transcription factor, which, following proteolytic cleavage, translocates to the nucleus and is required for transcription of the acute phase reactants C-reactive protein and serum amyloid P-component. We have recently demonstrated that long chain fatty acids increase CREBh gene and protein expression, the former via transcriptional mechanisms that are dependent on an intact proteasome and independent of cellular metabolism. Thus, CREBh may represent an important link between elevated lipids, inflammation and metabolic disease. However, the specific mechanism(s) by which fatty acids activate CREBh is unknown. Given that fatty acid metabolism is not required for CREBh induction, the specific target of fatty acids likely include a factor(s) that acts independently of cellular metabolism. Toll-Like Receptors (TLR), in particular TLR4, play a critical role in innate immunity, and can be activated by the lipid component of lipopolysaccharide (LPS). Recent data demonstrate that fatty acid-induced insulin resistance and inflammation in adipocytes, skeletal muscle, and endothelial cells is prevented following inhibition of TLR4 signaling. In the liver, several cell types express TLR4 and/or TLR2, including Kupffer cells, stellate cells and hepatocytes. Recent data suggest that TLR4 signaling plays a pivotal role in hepatic steatosis and liver damage, and preliminary data from our laboratory indicate that TLR4 activation via LPS induces CREBh gene expression in H4IIE liver cells. Thus, we hypothesize that TLR4 mediates fatty acid regulation of CREBh. Experiments in the current proposal are designed to directly test this hypothesis.