Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide and affects nearly 40% of obese youth and up to 10% of the general pediatric population. Some features of NAFLD are similar in children and adults, yet fibrosis and inflammation are more common in the portal zone and occur earlier in pediatric NAFLD patients than adults. This portends a rapid progression to end-stage liver disease in early adulthood. For the majority of children with NAFLD, mechanisms driving the origin and rapid progression of disease remain unknown. Thus, there is a critical, unmet need to study the specific underlying patterns of metabolic and molecular changes in the liver underlying the development and progression unique to children with NAFLD. This proposal will test the hypotheses that children with NAFLD have excess glucose and lipid produced by the liver, that those events are regulated by specific variations in the amount and location of RNAs and proteins in liver, and that the concentration of specific micro-RNAs in the blood can be used as a biomarker for NAFLD in pediatric patients.
This project uses a cross-sectional design with a single testing period without a formal intervention (e.g., diet, drug, exercise) or natural follow-up period. Participants with nonalcoholic fatty liver disease (NAFLD), and age-matched control groups classified as either obese (Ob control) or normal weight (NW control) will complete all metabolic and descriptive tests, including blood analyses. The NAFLD group will also have a liver biopsy as part of their standard clinical care; a portion of the biopsy will be used for the research testing. The Ob and NW control groups will not undergo liver biopsy. To provide a set of reference liver samples to compare with the NAFLD group, we will enroll a "liver control" group, consisting of age-matched patients who are scheduled to have a cholecystectomy with liver biopsy or are undergoing liver resection for tumor removal.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
100
Measurement of glucose and insulin for calculation of insulin sensitivity
Oral consumption of deuterated water to measure incorporation of label into lipids
Oral consumption of 13C-labeled glycerol to measure incorporation into glucose
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
RECRUITINGDe novo lipogenesis
Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water
Time frame: Day 1
Gluconeogenesis
Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water
Time frame: Day 1
Serum microRNA
Abundance of microRNAs in serum using a broad profiling platform and real-time quantitative polymerase chain reaction tests for confirming individual miRNAs
Time frame: Day 1
Abundance of liver collagen
Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy
Time frame: Day 1
Liver mitochondrial flux
Reported as the fluorescent lifetime redox ratio (FLIRR), which is calculated from measurements of free and bound NADH and FAD in liver biopsy sections, using fluorescence lifetime imaging microscopy
Time frame: Day 1
Insulin sensitivity
Calculated value of insulin sensitivity, using the oral minimal model and serial concentrations of glucose and insulin during an oral sugar tolerance test
Time frame: Day 1
Targets of microRNA-122
Transcripts bound to microRNA-122, measured using high-throughput sequencing of cross- linked immunoprecipitates (HITS-CLIP)
Time frame: Day 1
Liver transcriptomics
Spatial distribution of messenger RNAs in liver biopsies
Time frame: Day 1
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