Extracellular vesicle cargo and risk of NAFLD and NASH in Latino youth

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PROJECT SUMMARY/ABSTRACT The prevalence of pediatric nonalcoholic fatty liver disease (NAFLD) is escalating in US youth, particularly in those of Latino ancestry. NAFLD in children is associated with poor long-term outcomes, including diabetes, cardiovascular disease, and higher liver-related morbidity and mortality in adulthood. Despite the clinical significance of pediatric NAFLD, the mechanisms underlying its pathogenesis are poorly understood. This lack of knowledge is a major obstacle to the development of effective treatment and prevention strategies. Emerging studies support a role for extracellular vesicles (EVs) in NAFLD. Circulating EVs can influence intracellular signaling, tissue injury and repair, and matrix remodeling in liver cells. Plasma EV levels discriminate between adult patients with NAFLD and nonalcoholic steatohepatitis (NASH), and are positively correlated with histological grade. We conducted a series of proof-of-principle studies that demonstrate: 1) distinctive protein signatures in plasma EVs isolated from Latino children with NAFLD, 2) NAFLD-specific signatures approximate non-NAFLD signatures following lifestyle intervention that reduced liver fat, and 3) isolation of hepatocyte- specific EVs showed enrichment of liver-specific proteins in NAFLD. To date, however, investigations of EVs in pediatric NAFLD are scarce, and the role of EV-derived cargo in NAFLD pathogenesis in youth remains unknown. Here we propose a strategy to characterize the biological role of EVs in pediatric NAFLD. In Aim 1, we will apply unbiased methods to study proteins and RNAs carried in circulating and hepatocyte-enriched EVs to derive characteristic signatures associated with NAFLD and NASH in Latino youth. In Aim 2, we will measure EV concentration and content in youth with NAFLD who experienced changes in hepatic fat fraction following two distinct intervention modalities (i.e., intensive lifestyle and bariatric surgery). Importantly in Aim 3, we propose a series of molecular experiments to obtain mechanistic insight into the functional aspects of EV cargo. The combination of these approaches is innovative; and the strategy comprises a novel and sequentially appropriate set of aims that has not previously been used to address potential mechanisms of pathogenesis in pediatric NAFLD. The focus on children is especially impactful due to the growing prevalence of NAFLD in this population, the association of pediatric NAFLD with poor health outcomes in adulthood, and the expected future economic burden to care for these individuals. The focus on Latino children as an underrepresented yet growing population demographic is critical, because at every stage of life and along the entire NAFLD spectrum, Latinos experience a disproportionate burden of disease. The identification of EV-derived cargo associated with pediatric NAFLD will enhance our understanding of the biological mechanisms contributing to disease pathogenesis, provide a means to improve diagnostic and therapeutic strategies, and identify new targets for potential drug development.