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 HIV 感染者发病和死亡的主要原因。许多此类病例都与丙型肝炎病毒 (HCV) 合并感染有关，但 HIV 感染也常见其他导致肝损伤的原因。阐明 HIV 感染患者（无论是否并发 HCV）导致肝病的因素对于寻求了解肝病发病机制的研究人员以及治疗这一大群患者的临床医生来说非常重要。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相关，这可能导致肝硬化和死亡，特别是对于 HIV/HCV 合并感染的患者。然而，对于 HIV 感染中脂肪变性的病因学知之甚少。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，对于基因 1 型 HCV 感染（在美国非常流行）的人来说，肥胖可能是比 HCV 感染更重要的原因。在没有HCV感染的情况下，肥胖是脂肪变性的常见原因；然而，内脏肥胖（即内脏周围脂肪组织的积累）可能是比总体体重更重要的脂肪变性风险因素。不同的研究表明，内脏肥胖的后果（炎症细胞因子增加、脂联素减少、胰岛素抵抗、循环游离脂肪酸增加或肠道源性内毒素的微生物易位）可能会诱发脂肪变性。这些潜在的介质还可以解释 HIV 感染（独立于内脏肥胖）和脂肪变性之间的拟议联系。 HIV 复制与炎症标志物升高有关； HIV相关的外周脂肪萎缩伴随脂联素水平降低。 HIV 感染还与肠道相关淋巴组织的耗竭有关，导致“肠漏”和微生物易位。因此，有理由相信，HIV 感染将是脂肪变性的一个重要危险因素，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）将比没有感染的人更严重地发生脂肪变性；（1.2）内脏肥胖增加将与脂肪变性的严重程度相关；（1.3）外周脂肪萎缩和肠道相关微生物易位将是与HIV感染者脂肪变性相关的主导因素 (2.1) 在控制了 HIV、HCV 和内脏肥胖后，胰岛素抵抗仍将与脂肪变性的严重程度密切相关；(2.2) 循环游离脂肪酸水平将是脂肪变性的主要预测因子，因为内脏肥胖增加导致游离脂肪酸流向肝脏增加，并且在 HIV 相关皮下脂肪的情况下无法储存脂肪酸 组织损失；(2.3) 脂联素水平降低（由于 HIV 相关的脂肪萎缩和炎症）将解释 HIV 对脂肪变性的影响的很大一部分；(3.1) 由于脂肪变性严重程度增加，HIV/HCV 合并感染者比 HCV 单一感染患者的组织学脂肪性肝炎和纤维化的患病率和程度更高；(3.2) 增加 炎症、脂联素减少、游离脂肪酸增加和胰岛素抵抗将解释与 HCV 单一感染患者相比，HIV/HCV 合并感染患者组织学脂肪性肝炎和纤维化的患病率和程度更高。本研究的目的是确定脂肪变性的主要生物介质，以便将未来的机制和介入研究重点放在与脂肪变性发病机制及其进展相关的关键途径上。为了实现这一目标，将对 300 名男性和 100 名女性 HIV 和 HCV 单一感染、HIV/HCV 双重感染以及两者均未感染进行研究。最先进的非侵入性磁共振波谱 (MRS) 将测量脂肪变性。 MRS 研究的区域比肝组织的随机核心活检更大，提供肝脏脂肪的连续测量，并允许研究 HIV 单一感染和两种感染的患者；对于没有慢性肝病的患者，没有临床指征进行活检。 公共卫生相关性：肝病是艾滋病毒感染者发病和死亡的主要原因。肝脏脂肪变性（或脂肪肝）是美国肝脏疾病的常见原因，并且是艾滋病毒感染者特别关注的问题。脂肪变性在 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，特别是在 HIV/HCV 合并感染者中。 HCV 感染似乎与脂肪变性直接相关，但 HIV 脂肪变性的病因仍不清楚。在没有病毒感染的情况下，肥胖（特别是内脏肥胖）似乎是脂肪变性的关键促进因素。研究表明，美国大约 50% 的 HIV 感染者和 75% 的未感染者超重或肥胖。因此，了解 HIV、HCV 和内脏肥胖与脂肪变性的关系至关重要，并确定脂肪变性发病机制中的生物介质（微生物易位、炎症、脂肪因子和代谢改变），以便开发和研究针对主导因素的干预措施。