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.
