Nutrigenetic Intervention to Reduce Liver Fat in Hispanics

 描述(申请人提供)：据估计，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)。很少有研究检验降低升高的肝脂(ELF)的治疗策略的有效性，也没有针对西班牙裔儿童和青少年的研究。因此，除了对减肥的一般建议外，没有治疗儿童NAFLD或减少ELF的具体指南。此外，最近一项针对成年人的全基因组关联研究发现，PNPLA3基因的一个变异是一种新的因素，可以解释拉美裔人肝脏脂肪的增加，但还没有研究评估作为PNPLA3基因功能的ELF治疗的疗效。在初步数据中，我们发现，携带PNPLA3基因GG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；以及b)在高饮食糖的情况下，更容易出现肝脏脂肪堆积。后者的发现与最近在小鼠身上发表的一项研究和我们目前对PNPLA3的功能和调节的理解是一致的，尽管有限。综上所述，这些观察表明，不同的饮食策略在降低肝脏脂肪方面可能有不同的效果，这取决于PNPLA3基因。因此，我们的总体目标是找出针对肝脏脂肪沉积机制的新干预措施，而不是依赖于减肥，后者通常难以实现且具有挑战性。因此，我们建议进行一项随机试验，以测试饮食减糖对改善西班牙裔肥胖儿童和青少年肝脏脂肪含量的有效性，并检查这种方法的效果是否因PNPLA3基因而异。我们将招募120名临床诊断为NAFLD的拉美裔(10-18岁)患者，并在体重稳定的情况下随机对他们进行为期16周的干预：1)健康饮食的标准护理建议(对照组/安慰剂组)；2)减少饮食中的糖分(治疗组)。干预前后将测量以下指标：总肝脏脂肪、肝纤维化、内脏和皮下脂肪组织体积，用3特斯拉的磁共振成像方法测量；用DEXA测量全身脂肪；血浆肝酶、空腹胰岛素、葡萄糖、脂类、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挑战的反应。这些假设是：a)肝脏脂肪含量和代谢结果，如脂质和炎性生物标志物，将显示出与对照组相比显著的改善；以及b)与CC/CG个体相比，GG受试者在肝脏脂肪减少和代谢结果方面将观察到更大的益处。这些结果将为西班牙裔肥胖儿童和青少年ELF的新治疗策略提供疗效数据，并有可能影响西班牙裔治疗和预防NAFLD的个性化饮食建议，这是遗传易感性的一项功能。

 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.