PROJECT SUMMARY: Non-alcoholic fatty liver disease (NAFLD), once rarely observed in children and
adolescents, is now the most common form of liver disease in this age group. If untreated, NAFLD can
progress rapidly from simple fat infiltration to advanced stages of the disease including steatohepatitis, fibrosis,
and cirrhosis ultimately requiring liver transplantation. It has been reported that approximately 20% of patients
with NASH will progress to cirrhosis and liver failure. However, patients with NAFLD universally have hepatic
insulin resistance placing them at high risk of developing glucose intolerance and type 2 diabetes (T2D). The
pathogenesis of hepatic insulin resistance is closely tied to lipid accumulation, suggesting that depletion of
hepatic lipid is critical in the prevention of T2D in pediatric populations. Currently, no pharmaceutical treatment
exists to directly reverse NAFLD and limited progress has been made to identify effective, non-invasive
treatment. Because lifestyle changes remain the mainstay therapy for children with NAFLD, there is urgent
need for evidenced-based guidelines on the optimal dietary approaches to safely and effectively reverse
disease course. If fatty liver and insulin resistance can be reversed during the developmental adolescent
years, it may be possible to prevent progression of the disease to advanced stages and prevent occurrence of
other diseases such as T2D and CVD. Our preliminary data in 23 adolescents with NAFLD suggest that a
weight-maintaining, low glycemic, moderately CHO-restricted diet (~100 g CHO/day) significantly improves
both hepatic steatosis and hepatic insulin sensitivity. After 8 weeks, we found the CHO-restricted diet resulted
in significant reduction in hepatic lipid content (-6.0±4.7%, p<0.001), whereas no change in hepatic lipid was
observed in the fat-restricted (control) diet group. HOMA-IR, an index of hepatic insulin resistance, was
reduced (improved) (-1.2±5.1, <0.05) in the CHO-restricted group, and increased (worsened) slightly in the fat-
restricted (control) diet group. While these results are encouraging, this study needs to be verified in a larger
sample before translation to clinical practice can be recommended. It is also critical to measure hepatic insulin
sensitivity using accepted, rigorous methods to determine if the reduction in hepatic lipid is associated with
improvement in hepatic insulin sensitivity. Further, data identifying the changes in biological processes, such
as de novo lipogenesis, β-oxidation and lipid metabolism, that lead to depletion in liver fat in response to a
energy balanced CHO-restricted diet in the absence of significant weight loss in pediatric populations are
needed. The proposed study will address these gaps in knowledge using a 6 month family-based intervention
with 2 phases, a 12-week controlled feeding phase and a 12-week free living phase, to examine the effects of
two weight maintaining diets (moderately CHO-restricted vs fat-restricted diet) on depletion of hepatic lipid
content, improvement in hepatic insulin sensitivity, and changes in the plasma metabolome in adolescents with
NAFLD.
