Viral Hepatitis C and Lipid Homeostasis

丙型肝炎病毒与脂质稳态

• 批准号: 7551986
• 负责人: ALEEM SIDDIQUI
• 金额: $ 32.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7551986
• 关键词: ADD-1 protein; Address; Affect; Anabolism; Antiviral Agents; Apolipoproteins B; Binding Proteins; Calcium Signaling; Cell Nucleus; Cells; Cholesterol; Chronic Hepatitis; Chronic Hepatitis C; Cleaved cell; Complex; Event; Fatty Acids; Fatty Liver; Future; Gene Expression; Genes; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Histologic; Homeostasis; Individual; Integral Membrane Protein; Intervention; Lead; Lipids; Liver; Liver diseases; Membrane; Molecular; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phosphotransferases; Play; Population; Protein Biosynthesis; Proteins; RNA replication; RXR; Regulation; Regulatory Element; Replicon; Role; Scheme; Signal Transduction; Sterols; System; Transcriptional Regulation; Triglycerides; Very low density lipoprotein; Viral Proteins; Viral hepatitis; Work; apolipoprotein B-100; biological adaptation to stress; design; fatty acid biosynthesis; fatty acid metabolism; hepatitis C virus NS-5A protein; insight; lipid biosynthesis; lipid metabolism; microsomal triglyceride transfer protein; particle; protein activation; protein protein interaction; receptor; transcription factor; viral RNA

DESCRIPTION (provided by applicant): About 2-3% of the world population is infected with hepatitis C virus (HCV). Majority of HCV infections lead to chronic hepatitis. Hepatic steatosis (fatty liver) is recognized as a common histologic feature of chronic hepatitis C and occurs at an average rate of 50%. At molecular level, we and others have observed that HCV gene expression leads to alteration of cellular lipid metabolism. These changes manifest in elevated expression of genes involved in cholesterol/fatty acid biosynthetic pathways. In the current application, we propose investigate the role of HCV-induced oxidative stress in the activation of transcription factors, which include sterol regulatory element binding proteins (SREBP), liver X receptor, (LXR), PPAR1 and PCG-12. Attempts will be made to identify individual HCV gene product(s) playing a key role in steatosis. We further propose to investigate the mechanisms by which HCV gene expression impairs the lipidation of apolipoprotein B-100 (apoB). ApoB represents the major structural component of VLDL. Our recent studies identified the possible ternary complex composed of HCV NS5a protein, apoB and microsomal triglyceride transfer protein (MTP). Whether these protein-protein interactions lead to intervention of apoB lipidation will be investigated. Other possible mechanisms leading to the block in the secretion of apoB will be investigated. The results of these studies will provide unique insight into the ability of HCV gene expression in affecting lipid homeostasis and likely guide the design of future antiviral strategies in the treatment of liver disease associated with HCV infection.

描述（由申请人提供）：大约2-3％的世界人口感染了丙型肝炎病毒（HCV）。大多数HCV感染导致慢性肝炎。肝脂肪变性（脂肪肝）被认为是慢性肝炎的常见组织学特征，并以50％的平均速率发生。在分子水平上，我们和其他人观察到HCV基因表达会导致细胞脂质代谢的改变。这些变化体现在与胆固醇/脂肪酸生物合成途径有关的基因表达升高中。在当前的应用中，我们提出了研究HCV诱导的氧化应激在转录因子激活中的作用，包括固醇调节元件结合蛋白（SREBP），肝X受体，（LXR），PPAR1和PCG-12。将尝试确定单个HCV基因产品在脂肪变性中起关键作用。我们进一步建议研究HCV基因表达会损害载脂蛋白B-100（APOB）脂化的机制。 APOB代表VLDL的主要结构成分。我们最近的研究确定了由HCV NS5A蛋白，APOB和微粒体甘油三酸酯转移蛋白（MTP）组成的可能的三元复合物。这些蛋白质蛋白相互作用是否会导致APOB脂质的干预。将研究导致APOB分泌障碍的其他可能机制。这些研究的结果将为HCV基因表达影响脂质稳态的能力提供独特的见解，并可能指导未来的抗病毒药策略在治疗与HCV感染相关的肝病治疗中的设计。