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（由适用提供）：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病（NAFLD）。很少有研究检查了减少升高肝脂肪（ELF）的治疗策略的有效性，没有对西班牙裔儿童和青少年进行研究。因此，除了减肥的一般建议外，没有针对儿科NAFLD治疗小儿NAFLD或减少精灵的具体准则。此外，在成年人中进行的一项全基因组关联研究将PNPLA3基因中的一种变体确定为一种新的因素，解释了西班牙裔肝脏脂肪增加的新因素，但是没有研究评估ELF治疗作为PNPLA3基因型的功能的有效性。在初步数据中，我们表明，与CC和CG个体相比，携带PNPLA3的GG基因型的肥胖西班牙裔儿童和青少年的肝脏脂肪高2倍； b）在高饮食糖中更容易受到肝脏脂肪积累的影响。这一发现与最近在小鼠中发表的研究以及我们当前（尽管有限的）对PNPLA3的功能和调节的理解相吻合。综上所述，这些观察结果表明，不同的饮食策略可能会对减少肝脏脂肪产生不同的影响，具体取决于PNPLA3基因型。因此，我们的总体目标是确定针对肝脏脂肪沉积机制而不是依靠体重减轻的新颖干预措施，这通常很难实现和挑战以维持。因此，我们建议进行一项随机试验，以测试减少饮食糖的有效性，以改善肥胖的西班牙裔儿童和青少年的肝脏脂肪含量，并检查这种方法的影响是否因PNPLA3基因型而有所不同。我们将招募120名西班牙裔（10 - 18年），并在临床上诊断出NAFLD，并将其随机在体重稳定条件下进行16周干预措施：1）健康饮食的护理标准建议（控制/安慰剂组）； 2）减少饮食糖（治疗组）。以下将在干预之前和之后测量：总肝脂肪，肝纤维化，内脏和皮下脂肪组织的体积通过3泰斯拉的磁共振成像方法； Dexa的全身脂肪；血浆肝酶，禁食胰岛素，葡萄糖，脂质，游离脂肪酸和炎性标记物以及胰岛素和葡萄糖对口服葡萄糖挑战的反应。假设是：a）肝脏脂肪含量和代谢结局，例如脂质和炎症生物标志物，将显示出相对于对照而减少糖的改善； b）相对于CC/CG个体，将观察到GG受试者的肝脏脂肪降低和代谢结果的更大益处。这些结果将为肥胖的西班牙裔儿童和青少年的精灵提供新的治疗策略的有效性数据，并有可能影响个性化的饮食建议，以作为遗传倾向的西班牙裔治疗和预防NAFLD的治疗和预防NAFLD。