Hepatic Lipase and HCV Infection

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染全球1.7亿人，严重损害全球健康。慢性丙型肝炎病毒感染引起的疾病包括急性和慢性肝炎、肝硬变和肝细胞癌。丙型肝炎病毒感染还与患者脂肪肝(脂肪变性)的高患病率相关，这可能是许多代谢紊乱的原因，如胰岛素抵抗和糖尿病。聚乙二醇化干扰素-a和利巴韦林联合治疗可抑制40-80%患者的丙型肝炎病毒复制。然而，这种治疗伴随着严重的副作用，导致患者依从性差。出于这些原因，开发有效的疫苗和替代疗法是至关重要的，如果不更好地了解丙型肝炎病毒病毒学，这一目标是不可能实现的。有趣的是，最近的研究将宿主胆固醇和脂肪酸代谢途径与丙型肝炎病毒的生命周期联系起来。我们已经报道，丙型肝炎病毒感染上调脂肪酸合成酶(FASN)，这是进行新生脂肪生成的关键酶。我们还证明了丙型肝炎病毒感染需要FASN活性。随后我们发现，感染了丙型肝炎病毒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，并通过与肝细胞表面的硫酸肝素蛋白多糖(HSPG)的结合来促进脂质的摄取。由于已知HSPG介导了丙型肝炎病毒的初始附着，循环中的丙型肝炎病毒与脂蛋白结合，我们推测HL和LPL水平的升高可能以细胞结合或分泌的形式调节丙型肝炎病毒的感染和产生。有两个特定的目的被设计来解决这一假设：(I)确定细胞结合的HL和LPL在丙型肝炎病毒感染中的作用。(Ii)评价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与丙型肝炎病毒相关的脂肪变性，并对开发新的抗病毒治疗药物具有重要意义。公共卫生相关性：慢性丙型肝炎病毒感染与较低的血浆胆固醇水平和肝脏中脂肪堆积(脂肪变性)密切相关，由于与肥胖和胰岛素抵抗糖尿病密切相关，这种状态在许多肝脏疾病之前出现。这项拟议研究的完成将有助于我们理解丙型肝炎相关脂肪变性和丙型肝炎病毒生命周期的潜在机制。这些知识对于未来新的抗病毒疗法的开发至关重要。

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.