Hepatic Lipase and HCV Infection

描述（由申请人提供）：全球有1.7亿人感染丙型肝炎病毒（HCV），并对全球健康造成严重影响。慢性丙肝病毒感染引起的疾病包括急性和慢性肝炎、肝硬化和肝细胞癌。丙型肝炎病毒感染还与患者中脂肪肝（脂肪变性）的高患病率相关，这可能是胰岛素抵抗和糖尿病等许多代谢紊乱的原因。聚乙二醇修饰IFN-a和利巴韦林联合治疗可抑制40-80%患者的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，如果不更好地了解丙型肝炎病毒病毒学，这一目标就无法实现。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。我们已经报道了HCV感染上调脂肪酸合成酶（FASN），这是进行从头脂肪生成的关键酶。我们还证明HCV感染需要FASN活性。随后，我们发现HCV感染的人肝癌细胞增加了肝脂肪酶（HL）和脂蛋白脂肪酶（LPL）的表达，这两种酶都是维持循环脂蛋白水平的关键酶，并通过与肝细胞表面硫酸肝素蛋白聚糖（HSPG）的关联促进脂质摄取。由于已知HSPG介导初始HCV附着，循环HCV与脂蛋白相关，我们假设HL和LPL水平升高可能以细胞结合形式或分泌形式调节HCV感染和生成。有两个特定的目的旨在解决这一假设：(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。实现这些目标将有助于更好地了解丙型肝炎病毒的生命周期和丙型肝炎病毒相关的脂肪变性，并对开发新型抗病毒疗法具有指导意义。公共卫生相关性：慢性丙型肝炎病毒感染与血浆胆固醇水平降低和肝脏脂肪积累（脂肪变性）密切相关，脂肪变性与肥胖和胰岛素抵抗型糖尿病密切相关，是许多肝脏疾病的前兆。这项研究的完成将有助于我们理解HCV相关脂肪变性的潜在机制和HCV生命周期。这些知识对于未来新型抗病毒疗法的发展至关重要。

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.