Non-alcoholic fatty liver disease (NAFLD) is the most common chronic pediatric liver disease and may progress to an aggressive necro-inflammatory disease (NASH) that leads to fibrosis and cirrhosis in up to 1/3 of affected individuals. The disease mechanisms leading to NAFLD pathogenesis are complex and incompletely understood. Recent evidence indicates a potential link between NASH and obstructive sleep apnea (OSA), both common co-morbidities of obesity. Increased oxidative stress and elevated inflammatory markers occur in both diseases. Mice exposed to intermittent hypoxia, such as occurs in OSA, develop increased hepatic fat deposition. Elevated serum aminotransferases are seen in 20-50% of adults with OSA, and improve with CPAP therapy. Studies to date examining the relationship between NASH and OSA have focused on airflow limitation rather than the more physiologically important hypoxemia. Therefore, we propose the novel hypothesis that chronic intermittent hypoxemia caused by OSA plays a key role in the pathogenesis of NASH through the initiation of oxidative stress and up regulation of inflammatory pathways. To address this, we propose the following Aims: 1) to determine if OSA and nocturnal hypoxemia are associated with increasing severity of liver injury in pediatric NAFLD, 2) to determine if reactive oxygen species generation is associated with hypoxemia and severity of liver injury in pediatric NAFLD and 3) to determine if circulating inflammatory mediators are associated with hypoxemia and severity of liver injury in pediatric NAFLD. This will be investigated in children with biopsy proven NAFLD who will undergo sleep study and control subjects with OSA and/or hypoxemia. Research subjects will undergo testing of blood and urine for evidence of liver injury, metabolic abnormalities, oxidative stress and activation of inflammatory pathways. Changes in the degree of liver injury, oxidant injury and activation of inflammatory pathways will be assessed after correction of OSA/nocturnal hypoxemia. Complimentary to this research program, a five year mentored career development program is proposed that will incorporate both didactic and formal research training guided by two well established investigators with expertise in clinical and translational research in pediatric liver disease, oxidant injury and hypoxemia. The candidate's overarching career goal is to become an independent clinical/translational investigator who will identify novel mechanisms and treatments of NAFLD in children and adolescents. To achieve this goal, the candidate has developed a detailed plan that includes further training in immunology, hypoxemia and oxygen sensing, in vivo human metabolism, genetic and molecular epidemiology and longitudinal data analysis, with ongoing feedback from a formal Career Development Advisory Committee. The proposed research may provide new insights into mechanisms underlying liver injury in pediatric NASH and potentially translate into novel therapeutic and preventive strategies.

Public Health Relevance

NAFLD affects ~10% of the general and ~40% of the obese pediatric population. It is unclear what stimulates up to 1/3 of an estimated 1.6 million affected children to develop the more severe NASH. The proposed research will improve the understanding of the mechanistic pathways leading from benign fatty liver to NASH and stimulate new and more efficacious therapeutic strategies for children.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZDK1-GRB-7 (O3))
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Podskalny, Judith M,
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University of Colorado Denver
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United States
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Sullivan, J S; Le, M T; Pan, Z et al. (2015) Oral fructose absorption in obese children with non-alcoholic fatty liver disease. Pediatr Obes 10:188-95
Sundaram, Shikha S; Sokol, Ronald J; Capocelli, Kelley E et al. (2014) Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr 164:699-706.e1
Johnson, Richard J; Nakagawa, Takahiko; Sanchez-Lozada, L Gabriela et al. (2013) Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62:3307-15