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

项目总结 项目4.肝脏脂肪和纤维化在人类心血管疾病风险表型中的作用 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在美国困扰着8000万人，预计将成为 未来10年内的终末期肝病和肝移植。NAFLD，特别是它的进步 形式NASH与心血管疾病风险的增加相关，独立于常见的心血管疾病风险因素。这个 导致非酒精性脂肪肝和心血管疾病临床相关性的病理生理机制仍只存在。 部分地理解了。关于肝脂肪或肝纤维化的潜在作用的数据有限 NAFLD与心血管疾病风险的关系。项目4的中心目标是通过以下方式填补知识空白 无创性前瞻性评估心血管风险(CVR)表型(低风险与高风险) 对患有和不患有非酒精性脂肪肝的参与者的肝脏脂肪和纤维化含量进行量化。CVR表型将是 使用公认和有效的心血管风险评分进行评估：Framingham风险评分和冠状动脉 钙质分数。我们的团队开发了两种先进的磁共振成像技术并在临床上进行了验证 (MRI)无创性评估肝脏脂肪和纤维化的方法：磁共振质子密度脂肪分数(MRI- PDFF)和磁共振弹性成像(MRE)。为了验证UCSD队列中的发现，我们将与 使用受控衰减的Framingham心脏研究(FHS)的研究人员(DRS Ramachandran和Long) 参数(CAP)和振动控制弹性成像(VCTE)评估肝脏表型。项目4 还将探索CVD和NASH可能共有的几种致病机制。它还将作为 项目1、2和3中进行的机械学研究的翻译人类验证的中央枢纽和 提供从加州大学圣迭戈分校登记的患者那里获得预期收集的生物标本的途径。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人群心血管疾病风险的成像生物标记物。测试 分别由MRI-PDFF和MRE评估的肝脏脂肪含量和纤维化的假说分别是 与加州大学伯克利分校队列中非酒精性脂肪肝的心血管风险表型增加独立相关。验证这些 弗雷明翰心脏研究(FHS)中的关联。 目的2：探讨心血管疾病和非酒精性脂肪肝的共同发病机制。测试假设NAFLD 和CVD份额增加新生脂肪生成、肝纤维化或肝脏胆固醇代谢异常 作为共同的潜在机制。 目的3：OSE生物标记物可以在人群中区分NAFLD和CVD风险的测试假设 非酒精性脂肪肝患者。在与项目3的合作中，我们将测试OSE生物标志物与 非酒精性脂肪性肝病患者中的肝脏脂肪、纤维化和/或心血管危险表型。

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.