Visceral Adiposity, HIV, and HCV: Biologic Mediators of Hepatic Steatosis

内脏肥胖、HIV 和 HCV：肝脂肪变性的生物介质

• 批准号: 8292083
• 负责人: Phyllis C Tien
• 金额: $ 61.75万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292083
• 关键词: Address; Adipose tissue; Area; Biopsy; California; Central obesity; Cessation of life; Cirrhosis; Clinical; Collection; Core Biopsy; Data; Development; Disease; Endotoxins; Enrollment; Etiology; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Funding; Future; Genotype; Gut associated lymphoid tissue; HIV; HIV Infections; Health; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Histologic; Histology; Individual; Infection; Inflammation; Inflammatory; Injury; Insulin Resistance; Intervention; Lead; Link; Lipoatrophy; Liver; Liver diseases; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediator of activation protein; Medical center; Metabolic; Morbidity - disease rate; Nonesterified Fatty Acids; Obesity; Overweight; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Prevalence; Relative (related person); Research Personnel; Risk Factors; Sampling; San Francisco; Severities; Sex Characteristics; Site; Staging; Steatohepatitis; Techniques; Time; Tissues; United States; Veterans; Virus Diseases; Viscera; Visceral; Woman; adiponectin; antiretroviral therapy; base; chronic liver disease; cohort; comparison group; cytokine; inflammatory marker; liver biopsy; meetings; men; microbial; mortality; promoter; public health relevance; subcutaneous

DESCRIPTION (provided by applicant): Liver disease is a leading cause of morbidity and mortality in HIV-infected persons. Hepatitis C virus (HCV) coinfection is implicated in many of these cases, but other causes of liver injury are common in HIV infection. Elucidation of the factors responsible for liver disease among HIV-infected patients, with or without concurrent HCV is important for researchers who seek to understand the pathogenesis of liver disease, and for clinicians who treat this large group of patients. Hepatic steatosis (or fatty liver) is common in HIV infection and is associated with accelerated fibrosis progression, which can lead to cirrhosis and death, particularly in those with HIV/HCV coinfection. However, relatively little is known about the etiology of steatosis in HIV infection. In HCV infection, genotype 3 appears to be directly associated with steatosis, but is uncommon in the US. By contrast, in those with genotype 1 HCV infection (which is highly prevalent in the US), obesity may be a more important cause than HCV infection. In the absence of HCV infection, obesity is a common cause of steatosis; however, visceral obesity (which is the accumulation of adipose tissue around the viscera) may be a more important risk factor than overall body mass for steatosis. Different studies suggest that the consequences of visceral obesity (increased inflammatory cytokines, decreased adiponectin, insulin resistance, increased circulating free fatty acids or microbial translocation of gut-derived endotoxins) may induce steatosis. These potential mediators could also explain the proposed link between HIV infection (independent of visceral obesity) and steatosis. HIV replication has been associated with elevations in inflammatory markers; HIV- associated peripheral lipoatrophy with decreased adiponectin levels. HIV infection has also been associated with depletion of gut-associated lymphoid tissue leading to a "leaky gut" and microbial translocation. Thus there is reason to believe that HIV infection will be an important risk factor for steatosis, independent of HCV and visceral adiposity. We propose the following hypotheses: (1.1) HIV infection (alone or in combination with HCV) will be associated with a greater severity of steatosis than in those with neither infection;(1.2) Increased visceral adiposity will be associated with severity of steatosis;(1.3) Peripheral lipoatrophy and gut-associated microbial translocation will be the dominant factors associated with steatosis in HIV-infected patients;(2.1) After controlling for HIV, HCV, and visceral adiposity, insulin resistance will remain strongly associated with the severity of steatosis;(2.2) Circulating free fatty acid levels will be a dominant predictor of steatosis due to the increased free fatty acid flux to the liver from increased visceral adiposity and the inability to store fatty acids in the setting of HIV-associated subcutaneous adipose tissue loss;(2.3) Decreased adiponectin levels (due to HIV-associated lipoatrophy and inflammation) will explain a significant proportion of the HIV effect on steatosis;(3.1) HIV/HCV-coinfected will have a greater prevalence and degree of histologic steatohepatitis and fibrosis than HCV-monoinfected patients, due to an increased severity of steatosis;(3.2) Increased inflammation, decreased adiponectin, increased free fatty acids, and insulin resistance will explain the greater prevalence and degree of histologic steatohepatitis and fibrosis in HIV/HCV-coinfected compared to HCV- monoinfected patients. The objective of the proposed study is to identify the dominant biologic mediators of steatosis, in order to focus future mechanistic and interventional studies on the key pathways associated with the pathogenesis of steatosis and its progression. To accomplish this, 300 men and 100 women with HIV and HCV monoinfection, HIV/HCV coinfection and neither infection will be studied. State-of-the-art non-invasive magnetic resonance spectroscopy (MRS) will measure steatosis. MRS studies a larger area than a random core biopsy of liver tissue, provides a continuous measure of liver fat, and allows for the study of patients with HIV monoinfection and neither infection; biopsy is not clinically indicated in those without chronic liver disease. PUBLIC HEALTH RELEVANCE: Liver disease is a leading cause of morbidity and mortality in HIV-infected persons. Hepatic steatosis (or fatty liver) is a frequent cause of liver disease in the US and is a particular concern for HIV-infected persons. Steatosis is common in HIV infection and is associated with accelerated fibrosis progression, which can lead to cirrhosis and death, particularly in HIV/HCV-coinfected persons. HCV infection appears directly associated with steatosis, but the etiology of steatosis in HIV remains unclear. Obesity (in particular, visceral obesity) appears to be a key promoter of steatosis in the absence of viral infection. Studies show that about 50% of HIV-infected and 75% of HIV-uninfected persons in the US are overweight or obese. It is therefore critical to understand the relation of HIV, HCV, and visceral adiposity with steatosis, and to identify biologic mediators (microbial translocation, inflammation, adipokine and metabolic alterations) in the pathogenesis of steatosis, so that interventions targeted to the dominant factors can be developed and studied.

描述（由申请人提供）：肝病是艾滋病毒感染者发病和死亡率的主要原因。丙型肝炎病毒（HCV）共感染与许多病例有关，但肝损伤的其他原因在HIV感染中很常见。阐明艾滋病毒感染患者，有或没有并发HCV的因素，对于试图了解肝病发病机理的研究人员以及对治疗这一大型患者的临床医生而言，重要的是重要。肝脂肪变性（或脂肪肝）在HIV感染中很常见，并且与加速纤维化进展有关，这可能导致肝硬化和死亡，尤其是在HIV/HCV共感染的纤维中。然而，关于艾滋病毒感染中脂肪变性的病因相对较少。在HCV感染中，基因型3似乎与脂肪变性直接相关，但在美国并不常见。相比之下，在患有基因型1 HCV感染的患者中（在美国高度普遍），肥胖可能比HCV感染更重要。在没有HCV感染的情况下，肥胖是脂肪变性的常见原因。但是，内脏肥胖症（这是内脏周围的脂肪组织的积累）可能比脂肪变性的整体体重更重要。不同的研究表明，内脏肥胖症的后果（炎性细胞因子增加，脂联素降低，胰岛素抵抗，循环游离脂肪酸增加或肠源性内毒素的微生物易位）可能诱导脂肪变性。这些潜在的介体还可以解释艾滋病毒感染（与内脏肥胖无关）和脂肪变性之间提出的联系。艾滋病毒复制与炎症标记的升高有关。 HIV相关的外周脂质脂肪素水平降低。 HIV感染也与肠道相关淋巴组织的耗竭有关，导致“肠道渗漏”和微生物易位。因此，有理由相信HIV感染将是脂肪变性的重要危险因素，与HCV和内脏肥胖无关。我们提出以下假设：（1.1）HIV感染（单独或与HCV联合使用）将与脂肪变性更严重相比，与既没有感染的脂肪症相比；（1.2）内脏肥胖的增加将与脂肪变性的严重程度有关；（1.3）（1.3）（1.3）（1.3）外周脂肪症和肠道相关的微生物转化与构成的hHIV相关的是，hHIV是构成众所周知的占主导地位构成的占主导地位构成的占主导地位构成构成的偏见，那么构成了众所周两位的偏见。 patients;(2.1) After controlling for HIV, HCV, and visceral adiposity, insulin resistance will remain strongly associated with the severity of steatosis;(2.2) Circulating free fatty acid levels will be a dominant predictor of steatosis due to the increased free fatty acid flux to the liver from increased visceral adiposity and the inability to store fatty acids in the setting of HIV-associated subcutaneous adipose组织丧失；（2.3）脂联素水平降低（由于HIV相关的脂肪植物和炎症引起的）将解释HIV对脂肪变性的很大一部分；（3.1）HIV/HCV被染别的人将具有更大的患者和纤维化的患者，比起hcv-mono的患者（3. a a an fation Annofection）的患者（增长）更大。炎症，脂联素降低，游离脂肪酸增加和胰岛素抵抗，将解释与HCV-单染色的患者相比，HIV/HCV细胞感染的组织学脂肪性肝炎的患病率和程度更高。拟议的研究的目的是确定脂肪变性的主要生物学介质，以将未来的机械和介入性研究集中在与脂肪变性及其进展相关的关键途径上。为此，将研究300名患有HIV和HCV单感染的男性和100名女性，HIV/HCV共感染，并且不会研究任何感染。最先进的非侵入性磁共振光谱（MRS）将测量脂肪变性。 MRS研究的面积比肝组织的随机核心活检更大，提供了连续的肝脏脂肪量度，并可以研究HIV单感染和既不感染的患者;在没有慢性肝病的患者中，活检未在临床上表明。 公共卫生相关性：肝病是艾滋病毒感染者发病和死亡率的主要原因。肝脂肪变性（或脂肪肝）是美国肝病的常见原因，对HIV感染者特别关注。脂肪变性在HIV感染中很常见，并且与加速的纤维化进展有关，这可能导致肝硬化和死亡，尤其是在HIV/HCV被感染的人中。 HCV感染似乎与脂肪变性直接相关，但HIV中脂肪变性的病因尚不清楚。在没有病毒感染的情况下，肥胖（尤其是内脏肥胖）似乎是脂肪变性的关键启动子。研究表明，在美国，约有50％的艾滋病毒感染者和75％的艾滋病毒未感染的人超重或肥胖。因此，重要的是要了解HIV，HCV和内脏肥胖与脂肪变性的关系，并在脂肪变性的发病机理中鉴定生物学介质（微生物易位，炎症，脂肪因子和代谢改变），因此可以开发和研究针对主要因素的干预措施。