Nutrigenetic Intervention to Reduce Liver Fat in Hispanics

 描述（由申请人提供）：估计近40%的肥胖西班牙裔儿童和青少年患有非酒精性脂肪肝（NAFLD）。很少有研究检查治疗策略对降低肝脏脂肪升高（ELF）的疗效，没有在西班牙裔儿童和青少年中进行研究。因此，除了减肥的一般建议外，没有治疗儿童NAFLD或减少ELF的具体指南。此外，最近在成人中进行的一项全基因组关联研究确定PNPLA 3基因中的一种变体是解释西班牙裔人肝脏脂肪增加的一个新因素，但没有研究评估ELF治疗的疗效作为PNPLA 3基因型的函数。在初步数据中，我们表明携带PNPLA 3 GG基因型的肥胖西班牙裔儿童和青少年：a）与CC和CG个体相比，肝脏脂肪高2倍以上;和B）在高膳食糖的背景下更容易发生肝脏脂肪积累。后者的发现与最近发表的小鼠研究以及我们目前对PNPLA 3功能和调节的理解（尽管有限）相吻合。总之，这些观察结果表明，不同的饮食策略可能对减少肝脏脂肪有不同的影响，这取决于PNPLA 3基因型。因此，我们的总体目标是找到针对肝脏脂肪沉积机制的新型干预措施，而不是依赖于减肥，因为减肥通常很难实现，而且难以维持。因此，我们建议进行一项随机试验，以测试饮食糖减少对改善肥胖西班牙裔儿童和青少年肝脏脂肪含量的疗效，并检查这种方法的效果是否因PNPLA 3基因型而异。我们将招募120名临床诊断为NAFLD的西班牙裔（10-18岁），并将他们随机分配到体重稳定条件下的16周干预措施：1）健康饮食的标准护理建议（对照组/安慰剂组）; 2）减少饮食糖（治疗组）。将在干预前后测量以下指标：总肝脂肪、肝纤维化、内脏和皮下腹部脂肪组织体积（通过磁共振成像方法在3特斯拉下测量）;全身脂肪（通过DEXA测量）;血浆肝酶、空腹胰岛素、葡萄糖、脂质、游离脂肪酸和炎症标志物，以及胰岛素和葡萄糖对口服葡萄糖激发的反应。假设是：a）肝脏脂肪含量和代谢结果，如脂质和炎性生物标志物，将显示相对于对照，糖减少的显著更大的改善;和B）相对于CC/CG个体，在GG受试者中将观察到肝脏脂肪减少和代谢结果的更大益处。这些结果将为肥胖西班牙裔儿童和青少年的ELF新治疗策略提供疗效数据，并有可能影响西班牙裔NAFLD治疗和预防的个性化饮食建议，作为遗传易感性的函数。

 DESCRIPTION (provided by applicant): Almost 40% of obese Hispanic children and adolescents are estimated to have non-alcoholic fatty liver disease (NAFLD). Very few studies have examined the efficacy of treatment strategies for reducing elevated liver fat (ELF), with no studies in Hispanic children and adolescents. Consequently, there are no specific guidelines for treating pediatric NAFLD or reducing ELF other than general advice for weight loss. In addition, a recent genome-wide association study in adults identified a variant in the PNPLA3 gene as a novel factor explaining increased liver fat in Hispanics, but there are no studies that have evaluated the efficacy of treatments for ELF as a function of PNPLA3 genotype. In preliminary data, we show that obese Hispanic children and adolescents who carry the GG genotype of PNPLA3: a) have > 2-fold higher liver fat compared to CC and CG individuals; and b) are more susceptible to liver fat accumulation in the context of high dietary sugar. This latter finding fit with a recently published study in mice and our current, though limited, understanding of the function and regulation of PNPLA3. Taken together, these observations suggest that different dietary strategies may have differential effects on reducing liver fat, depending on PNPLA3 genotype. Therefore, our overall objective is to identify novel interventions that target the mechanism of fat deposition in liver rather than rely on weight loss, which is typically difficult o achieve and challenging to sustain. We therefore propose to conduct a randomized trial to test the efficacy of dietary sugar reduction for improving liver fat content in obese Hispanic children and adolescents and examine whether the effects of this approach vary by PNPLA3 genotype. We will recruit 120 Hispanics (10-18 years) with clinically diagnosed NAFLD and randomize them to 16-week interventions under weight stable conditions: 1) standard of care advice for healthy eating (control/placebo group); and 2) reduction of dietary sugars (treatment group). The following will be measured before and after intervention: total liver fat, liver fibrosis, visceraland subcutaneous abdominal adipose tissue volume by magnetic resonance imaging methods at 3 Tesla; total body fat by DEXA; plasma liver enzymes, fasting insulin, glucose, lipids, free fatty acids, and inflammatory markers, and insulin and glucose response to an oral glucose challenge. The hypotheses are: a) liver fat content and metabolic outcomes, such as lipids and inflammatory biomarkers, will show significantly greater improvements with sugar reduction relative to control; and b) greater benefits in liver fat reduction and metabolic outcomes will be observed in GG subjects relative to CC/CG individuals. These results will provide efficacy data for a novel treatment strategy for ELF in obese Hispanic children and adolescents and has the potential to impact personalized dietary recommendations for treatment and prevention of NAFLD in Hispanics, as a function of genetic predisposition.