Hepatic Lipase and HCV Infection

肝脂肪酶和丙型肝炎病毒感染

• 批准号: 7700178
• 负责人: TONY WANG
• 金额: $ 21.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700178
• 关键词: Accounting; Acute; Address; Adverse effects; Alternative Therapies; Antiviral Agents; Antiviral Therapy; Binding; CD36 gene; Cell Culture Techniques; Cell surface; Cells; Cholesterol; Chronic Hepatitis; Chronic Hepatitis C; Cirrhosis; Combined Modality Therapy; Development; Diabetes Mellitus; Disease; Docking; Enzymes; Equilibrium; Excretory function; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Fibrosis; Future; Gland; Glycosaminoglycans; Goals; Health; Heparin; Hepatitis C; Hepatitis C virus; Hepatocyte; High Prevalence; Human; Hydrolysis; Infection; Insulin Resistance; Knowledge; Life Cycle Stages; Light; Link; Lipids; Lipolysis; Lipoproteins; Liver; Liver diseases; Mediating; Metabolic Diseases; Metabolic Pathway; Obesity; Pathogenesis; Pathway interactions; Patients; Phospholipids; Plasma; Plasma Cells; Polyethylene Glycols; Primary carcinoma of the liver cells; Production; RNA; RNA Interference; RNA replication; Reporting; Research; Ribavirin; Role; Site; Surface; Therapeutic; Tissues; Triglycerides; Up-Regulation; Vaccines; Viral; Viral Proteins; Virion; Virus; Virus Replication; Work; base; compliance behavior; design; heparin proteoglycan; hepatic lipase; hepatic sinusoid; hepatoma cell; lipid biosynthesis; lipoprotein cholesterol; lipoprotein lipase; novel; particle; public health relevance; sterol homeostasis; uptake; virology; virus host interaction

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects 170 million people worldwide and exacts a heavy toll on global health. Diseases caused by chronic HCV infection include acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HCV infection also correlates with high prevalence of fatty liver (steatosis) in patients, which may account for many metabolic disorders such as insulin resistance and diabetes mellitus. Combination therapy with polyethylene glycol modified IFN-a and ribavirin suppresses HCV replication in 40-80% of patients. However, severe side effects are associated with this treatment, leading to poor patient compliance. For these reasons, it is crucial to develop effective vaccine and alternative therapies, a goal that cannot be accomplished without a better understanding of the HCV virology. Interestingly, recent studies have linked host cholesterol and fatty acid metabolic pathways to HCV life cycle. We have reported that HCV infection upregulates fatty acid synthase (FASN), the key enzyme carrying out de novo lipogenesis. We also demonstrated that HCV infection requires FASN activity. Subsequently we found that HCV- infected human hepatoma cells increased their expressions of hepatic lipase (HL) and lipoprotein lipase (LPL), both of which are key enzymes in maintaining circulating lipoprotein levels and can facilitate lipid uptake via their associations with heparin sulphate proteoglycans (HSPG) on hepatocyte surface. Because it is known that HSPG mediates the initial HCV attachment and circulating HCV associates with lipoproteins, we hypothesize that elevated levels of HL and LPL may regulate the HCV infection and production in either cell-bound forms or secreted forms. Two specific aims are designed to address that hypothesis: (i) To determine the roles of cell-bound HL and LPL in HCV infection. (ii) To evaluate the effect of elevated HL and LPL activities on circulating virus infectivity. Accomplishing these objectives will provide a better understanding of HCV life cycle and the HCV-associated steatosis with implications for the development of novel antiviral therapeutics. PUBLIC HEALTH RELEVANCE: Chronic HCV infection strongly correlates with lower plasma cholesterol levels and the accumulation of fat in livers (steatosis), a state preceding many liver diseases owing to its intimate association with obesity and insulin-resistant diabetes mellitus. Completion of the proposed research will shed light to our understanding of the underlying mechanisms of HCV-associated steatosis and the HCV life cycle. Such knowledge is critical for the future development of novel antiviral therapies.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染全球1.7亿人，对全球健康造成严重影响。由慢性HCV感染引起的疾病包括急性和慢性肝炎、肝硬化和肝细胞癌。HCV感染还与患者脂肪肝（脂肪变性）的高患病率相关，这可能导致许多代谢紊乱，如胰岛素抵抗和糖尿病。用聚乙二醇修饰的IFN-α和利巴韦林的组合疗法在40-80%的患者中抑制HCV复制。然而，严重的副作用与这种治疗相关，导致患者依从性差。由于这些原因，开发有效的疫苗和替代疗法至关重要，如果不更好地了解HCV病毒学，就无法实现这一目标。有趣的是，最近的研究将宿主胆固醇和脂肪酸代谢途径与HCV生命周期联系起来。我们已经报道，HCV感染上调脂肪酸合成酶（FATIGUE），进行从头脂肪生成的关键酶。我们还证明了HCV感染需要FcR活性。随后，我们发现HCV感染的人肝癌细胞增加了肝脂酶（HL）和脂蛋白脂酶（LPL）的表达，这两种酶都是维持循环脂蛋白水平的关键酶，并且可以通过与肝细胞表面的硫酸肝素蛋白聚糖（HSPG）结合来促进脂质摄取。由于已知HSPG介导初始HCV附着和循环HCV与脂蛋白的结合，我们假设HL和LPL水平升高可能调节HCV感染和细胞结合形式或分泌形式的产生。两个具体的目的是为了解决这一假设：（i）确定细胞结合的HL和LPL在HCV感染中的作用。(ii)评估HL和LPL活性升高对循环病毒感染性的影响。实现这些目标将提供一个更好地了解HCV的生命周期和HCV相关的脂肪变性与发展的新的抗病毒治疗的影响。公共卫生关系：慢性HCV感染与较低的血浆胆固醇水平和肝脏中脂肪的积累（脂肪变性）密切相关，脂肪变性是许多肝脏疾病之前的状态，因为它与肥胖和胰岛素抵抗型糖尿病密切相关。这项研究的完成将有助于我们了解HCV相关脂肪变性和HCV生命周期的潜在机制。这些知识对于未来开发新的抗病毒疗法至关重要。