Fatty Acid Regulation of the Acute Inflammatory Response

描述（由申请人提供）：本申请的总体目的是：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。升高的血清和肝脏脂质是NAFLD的特征性特征，并且与该疾病中存在的局部和全身炎症有关。CREBh是最近鉴定的肝特异性内质网定位的转录因子，其在蛋白水解切割后易位至细胞核并且是急性期反应物C-反应蛋白和血清淀粉样蛋白P-组分的转录所需的。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，前者通过转录机制，依赖于一个完整的蛋白酶体和独立的细胞代谢。因此，CREBh可能代表了血脂升高、炎症和代谢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，脂肪酸的特异性靶标可能包括独立于细胞代谢起作用的因子。Toll样受体（TLR），特别是TLR 4，在先天免疫中起关键作用，并且可以被脂多糖（LPS）的脂质组分激活。最近的数据表明，脂肪酸诱导的胰岛素抵抗和脂肪细胞，骨骼肌和内皮细胞的炎症是防止TLR 4信号转导抑制后。在肝脏中，几种细胞类型表达TLR 4和/或TLR 2，包括枯否细胞、星状细胞和肝细胞。最近的数据表明，TLR 4信号转导在肝脂肪变性和肝损伤中起着关键作用，并且来自我们实验室的初步数据表明，通过LPS激活TLR 4诱导H4 IIE肝细胞中CREBh基因表达。因此，我们假设TLR 4介导CREBh的脂肪酸调节。本提案中的实验旨在直接检验这一假设。

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.