Nutrigenetic Intervention to Reduce Liver Fat in Hispanics

减少西班牙裔肝脏脂肪的营养遗传干预

• 批准号: 9010742
• 负责人: Hooman Allayee
• 金额: $ 78.09万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-24 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010742
• 关键词: Abdomen; Address; Adipose tissue; Adolescent; Adult; Animal Model; Beverages; Biological Markers; Biological Process; Body Weight decreased; Body fat; Calories; Child; Childhood; Cirrhosis; Clinical Research; Clinical Trials; Control Groups; Data; Data Analyses; Deposition; Diagnosis; Diet; Dietary Intervention; Dietary Sugars; Dual-Energy X-Ray Absorptiometry; Ensure; Enzymes; Equilibrium; Ethical Issues; Ethnic group; Fasting; Fatty acid glycerol esters; Frequencies; Genes; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Glucose; Goals; Guidelines; Healthy Eating; Hispanics; Individual; Inflammatory; Insulin; Intervention; Lead; Lipids; Liver; Liver Fibrosis; Liver diseases; Magnetic Resonance Elastography; Magnetic Resonance Imaging; Malignant neoplasm of liver; Measures; Metabolic; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Oral; Outcome; Overweight; Phospholipase; Placebo Control; Plasma; Populations at Risk; Predisposition; Prevalence; Prevention; Public Health; Publishing; Randomized; Recommendation; Recruitment Activity; Regulation; Reporting; Research Design; Risk; Scheme; Treatment Efficacy; Variant; Visceral; Weight; base; efficacy testing; genome wide association study; group intervention; imaging modality; improved; inflammatory marker; innovation; intervention effect; mouse model; non-alcoholic fatty liver; novel; nutrition related genetics; obesity in children; primary outcome; public health relevance; randomized trial; response; standard of care; subcutaneous; sugar; treatment group; treatment strategy; weight maintenance

 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.

 描述（由申请人提供）：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)，很少有研究探讨降低肝脏脂肪 (ELF) 治疗策略的有效性。没有对西班牙裔儿童和青少年进行测试，除了减肥的一般建议之外，没有治疗儿科 NAFLD 或减少 ELF 的具体指南。此外，最近的一项针对成人的全基因组关联研究发现了一种变异。 PNPLA3 基因是解释西班牙裔人肝脏脂肪增加的新因素，但没有研究评估 ELF 治疗效果与 PNPLA3 基因型的关系。在初步数据中，我们表明携带 GG 的肥胖西班牙裔儿童和青少年。 PNPLA3 基因型：a) 与 CC 和 CG 个体相比，肝脏脂肪含量高出 2 倍以上；b) 在高饮食糖的情况下更容易出现肝脏脂肪积累，后者的发现与最近发表的小鼠研究结果相符。和我们的尽管目前对 PNPLA3 功能和调节的了解有限，但这些观察结果表明，根据 PNPLA3 基因型，不同的饮食策略可能对减少肝脏脂肪产生不同的影响。肝脏中脂肪沉积的机制，而不是依赖于体重减轻，这通常很难实现且难以维持，因此我们建议进行一项随机试验，以测试饮食中减少糖分对改善肥胖西班牙裔儿童肝脏脂肪含量的功效。和青少年，并检查这是否会产生影响方法因 PNPLA3 基因型而异。我们将招募 120 名临床诊断为 NAFLD 的西班牙裔患者（10-18 岁），并在体重稳定的情况下将他们随机分配到为期 16 周的干预措施：1）健康饮食的标准护理建议（对照组/安慰剂组）； 2)减少膳食糖分（治疗组）在干预前后测量以下内容：通过磁共振成像方法测量肝脏总脂肪、肝纤维化、内脏和皮下腹部脂肪组织体积。 3 特斯拉；DEXA 测定的全身脂肪；血浆肝酶、空腹胰岛素、葡萄糖、脂质、游离脂肪酸和炎症标记物，以及胰岛素和葡萄糖对口服葡萄糖挑战的反应。与对照相比，代谢结果（例如脂质和炎症生物标志物）将显示出显着更大的改善；b）相对于 CC/CG 个体，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。为新疗法提供疗效数据西班牙裔肥胖儿童和青少年的 ELF 策略，并有可能影响西班牙裔 NAFLD 治疗和预防的个性化饮食建议，作为遗传倾向的函数。