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

项目摘要：非酒精性脂肪性肝病(NAFLD)，曾经很少在儿童和 青少年，现在是这个年龄段最常见的肝病形式。如果不治疗，NAFLD可以 从单纯的脂肪渗透迅速发展到疾病的晚期，包括脂肪性肝炎，纤维化， 和肝硬变最终需要肝移植。据报道，大约20%的患者 NASH将进展为肝硬变和肝功能衰竭。然而，NAFLD患者普遍有肝脏 胰岛素抵抗使他们处于发展为葡萄糖不耐受和2型糖尿病(T2D)的高风险。这个 肝脏胰岛素抵抗的发病机制与脂质堆积密切相关，提示肝脏胰岛素抵抗的耗竭 在儿童人群中，肝脂是预防T2D的关键。目前，没有药物治疗 存在直接逆转NAFLD的方法，在识别有效、非侵入性的方面取得的进展有限 治疗。由于改变生活方式仍然是治疗NAFLD儿童的主要方法，因此迫切需要 需要以证据为基础的最佳饮食方法指南，以安全有效地逆转 病程。发育期青春期脂肪肝和胰岛素抵抗能否逆转 多年来，有可能防止疾病的发展到晚期，并防止发生 其他疾病，如T2D和CVD。我们对23名患有NAFLD的青少年的初步数据表明， 保持体重，低血糖，适度限制Cho的饮食(~100克Cho/天)显著改善 肝脏脂肪变性和肝脏胰岛素敏感性。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&lt；0.001)，而肝脂无明显变化 在限脂(对照)饮食组观察到。HOMA-IR是肝脏胰岛素抵抗的指标， 胆固醇限制组降低(改善)(-1.2±5.1，t；0.05)，脂肪减少(恶化)。 限制(对照)饮食组。虽然这些结果令人鼓舞，但这项研究需要在更大的范围内进行验证 可推荐转化为临床实践前的样本。测量肝脏胰岛素也是至关重要的。 使用公认的、严格的方法来确定肝脂减少是否与 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 作为新的脂肪生成，β氧化和脂代谢，导致肝脏脂肪耗竭，以回应 在儿童人群中，在体重没有显著下降的情况下，能量平衡的CHO限制饮食是 需要的。这项拟议的研究将通过为期6个月的基于家庭的干预来解决这些知识差距 分两个阶段，12周控制喂养阶段和12周自由生活阶段，以检查 两种减肥饮食(适度限制胆固醇饮食和脂肪限制饮食)对肝脂消耗的影响 血清胰岛素水平、肝脏胰岛素敏感性的改善及血浆代谢产物的变化 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.