Moderately CHO-restricted diet as treatment targeting improvement in hepatic lipid and insulin sensitivity in adolescents with NAFLD

非酒精性脂肪性肝病（NAFLD），曾经很少在儿童中观察到， 青少年，现在是这个年龄组最常见的肝病形式。如果不治疗，NAFLD可以 从简单的脂肪浸润迅速进展到疾病的晚期，包括脂肪性肝炎，纤维化， 以及最终需要肝移植的肝硬化。据报道，大约20%的患者 NASH患者将发展为肝硬化和肝功能衰竭。然而，NAFLD患者普遍存在肝硬化， 胰岛素抵抗使他们处于发展葡萄糖耐受不良和2型糖尿病（T2 D）的高风险中。的 肝脏胰岛素抵抗的发病机制与脂质积累密切相关，这表明 肝脏脂质在预防儿科人群中的T2 D中至关重要。目前，没有药物治疗 存在直接逆转NAFLD的药物，但在确定有效的、非侵入性的 治疗由于生活方式的改变仍然是NAFLD儿童的主要治疗方法， 需要有关于最佳饮食方法的循证指南，以安全有效地扭转 病程。如果脂肪肝和胰岛素抵抗在青春期发育过程中可以逆转， 年，它可能会防止疾病进展到晚期阶段，并防止发生 其他疾病，如T2 D和CVD。我们对23名NAFLD青少年的初步数据表明， 维持体重、低血糖、中度CHO限制饮食（约100 g CHO/天）显著改善 肝脂肪变性和肝胰岛素敏感性。8周后，我们发现CHO限制饮食导致 肝脂含量显著降低（-6.0 ~4.7%，P<0.001），而肝脂含量无变化， 在脂肪限制（对照）饮食组中观察到。HOMA-IR是肝脏胰岛素抵抗的指标， 减少（改善）（-1.2 5. 1，<0.05）在CHO限制组，和增加（恶化）在脂肪- 控制饮食组。虽然这些结果令人鼓舞，但这项研究需要在更大范围内进行验证。 建议在转化为临床实践之前提供样本。测量肝脏胰岛素也很关键 使用公认的、严格的方法确定肝脂质降低是否与 改善肝脏胰岛素敏感性。此外，识别生物过程中的变化的数据，例如 由于新生脂肪生成、β-氧化和脂质代谢，导致肝脏脂肪消耗， 在儿科人群中，在没有显著体重减轻的情况下，能量平衡的CHO限制饮食是 needed.拟议的研究将通过6个月的家庭干预来解决这些知识差距 分为两个阶段，12周的控制喂养期和12周的自由生活期，以检查 两种体重维持饮食（中度限制CHO饮食vs限制脂肪饮食）对肝脂质消耗的影响 青少年胰岛素抵抗患者血浆胰岛素含量、肝脏胰岛素敏感性的改善和血浆代谢组的变化 NAFLD。

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.