Role of liver fat and fibrosis in human CVD risk phenotypes.

项目摘要 项目4。肝脏脂肪和纤维化在人类CVD风险表型中的作用 心血管疾病（CVD）是非酒精性脂肪肝患者死亡的主要原因 （NAFLD）。NAFLD在美国折磨着8000万人，预计将成为糖尿病的主要原因。 终末期肝病和肝移植在未来10年内。NAFLD，尤其是其进步的 NASH与CVD风险增加相关，独立于常见的CVD风险因素。的 导致NAFLD和CVD之间临床关联的病理生理机制仅 部分理解。关于肝脏脂肪或肝纤维化含量在其治疗中的潜在作用的数据有限。 与NAFLD中CVD风险相关。项目4的中心目标是填补这一知识空白， 前瞻性评估心血管风险（CVR）表型（低风险与高风险）， 量化有和没有NAFLD的参与者的肝脏脂肪和纤维化含量。CVR表型将 使用公认且有效的CVD风险评分进行评估：Fragrance风险评分和冠状动脉 钙含量。我们的团队已经开发并临床验证了两种先进的磁共振成像技术 (MRI)非侵入性评估肝脏脂肪和纤维化的方式：MRI质子密度脂肪分数（MRI- PDFF）和MR弹性成像（MRE）。为了验证UCSD队列中的发现，我们将与 使用受控衰减的FHS研究人员（Ramachandran和Long博士） 肝脏表型的参数（CAP）和振动控制弹性成像（VCTE）评估。项目4 还将探讨CVD和NASH可能共有的几种致病机制。它也将成为 在项目1、2和3中进行的机制研究的翻译人类验证的中心枢纽，以及 提供从UCSD入组的患者中前瞻性采集的生物标本的访问权限。为了实现我们的目标， 我们的具体目标是： 目的1：开发和验证NAFLD人群中CVD风险的成像生物标志物。测试 分别通过MRI-PDFF和MRE评估的肝脏脂肪含量和纤维化的假设， 与UCSD队列中NAFLD的CVD风险表型增加独立相关。验证这些 心脏病研究（FHS）。 目的2：研究CVD和NAFLD的共同机制。NAFLD的检验假设 和CVD共享增加的新生脂肪生成、肝纤维化或异常肝胆固醇代谢 作为共同的潜在机制。 目的3：检验假设OSE生物标志物可以区分人群中的NAFLD和CVD风险。 NAFLD患者。在与项目3的合作中，我们将测试OSE生物标志物与 NAFLD患者群体中的肝脂肪、纤维化和/或CVD风险表型。

PROJECT SUMMARY Project 4. Role of liver fat and fibrosis in human CVD risk phenotypes Cardiovascular disease (CVD) is the leading cause of mortality among individuals with nonalcoholic fatty liver (NAFLD). NAFLD afflicts 80 million persons in the United States and is projected to become the main cause of end-stage liver disease and liver transplantation within the next 10 years. NAFLD, and especially its progressive form NASH, is associated with an increase in CVD risk, independent of common CVD risk factors. The pathophysiological mechanisms that contribute to the clinical association between NAFLD and CVD remain only partially understood. There are limited data regarding the potential role of liver fat or liver fibrosis content in their association with CVD risk in NAFLD. The central objective of Project 4 is to fill this gap in knowledge by prospectively assessing the cardiovascular risk (CVR) phenotype (low risk versus high risk) by non-invasively quantifying liver fat and fibrosis content in participants with and without NAFLD. CVR phenotypes will be assessed using a well-accepted and validated CVD risk score: Framingham Risk Score and Coronary Artery Calcium score. Our group has developed and clinically validated two advanced magnetic resonance imaging (MRI) modalities for non-invasive assessment of liver fat and fibrosis: MRI Proton Density Fat Fraction (MRI- PDFF) and MR Elastography (MRE). To validate findings in the UCSD cohort, we will collaborate with investigators of the Framingham Heart Study (FHS) (Drs Ramachandran and Long) using Controlled Attenuation Parameter (CAP) and Vibration Controlled Elastography (VCTE) assessments for liver phenotyping. Project 4 will also explore several pathogenic mechanisms that may be shared by CVD and NASH. It will also serve as the central hub for translational human validation of mechanistic studies conducted in Projects 1, 2, and 3 and provide access to a prospectively collected biospecimens from patients enrolled at UCSD. To achieve our goal, our specific aims are: Aim 1: Development and validation of imaging biomarkers for CVD risk in the NAFLD population. Test the hypotheses that liver fat content and fibrosis, as assessed by MRI-PDFF and MRE, respectively, each are independently associated with increased CVD risk phenotypes in NAFLD in the UCSD cohort. Validate these associations in the Framingham Heart Study (FHS). Aim 2: Investigation of common mechanisms underlying CVD and NAFLD. Test hypotheses that NAFLD and CVD share increased de novo lipogenesis, hepatic fibrogenesis, or abnormal hepatic cholesterol metabolism as common underlying mechanisms. Aim 3: Test hypothesis that OSE biomarkers can differentiate NAFLD and CVD risk in a population of NAFLD patients. In collaboration with Project 3, we will test the hypothesis that OSE biomarkers associate with liver fat, fibrosis, and/or CVD risk phenotypes in a population of NAFLD patients.