Fatty Acid Desaturase 1 (FADS1) Variants and Non-alcoholic Fatty Liver Disease

脂肪酸去饱和酶 1 (FADS1) 变异体与非酒精性脂肪肝

• 批准号: 9106903
• 负责人: Wanqing Liu
• 金额: $ 40.5万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106903
• 关键词: Address; Affect; Alleles; Area; Biochemical; Biopsy; Blood; Cell Line; Chronic; Chronic Disease; Clinical Research; Clinical Trials; Data; Development; Diet; Dietary Factors; Disease; Disease Progression; Docosahexaenoic Acids; Drug Kinetics; Effectiveness; Eicosapentaenoic Acid; Enrollment; Enzymes; Etiology; Fatty Acid Desaturases; Fatty acid glycerol esters; Fibrosis; Fish Oils; Foundations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Hepatic; Hepatocyte; High Fat Diet; Histologic; Histology; Human; In Vitro; Individual; Inflammation; Intake; International; Intervention; Knockout Mice; Knowledge; Lipids; Liver; Liver diseases; Mammals; Mediating; Modeling; Morbidity - disease rate; Mus; N-3 polyunsaturated fatty acid; Natural History; Nutrient; Omega-3 Fatty Acids; Patients; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Polyunsaturated Fatty Acids; Population; Preventive; Research; Risk; Risk Factors; Role; Sampling; Serum; Severity of illness; Supplementation; Testing; Therapeutic; Time; Treatment outcome; Triglycerides; Variant; base; chronic liver disease; design; disease phenotype; disorder risk; effective therapy; enzyme activity; enzyme biosynthesis; evidence base; fatty acid metabolism; fatty acid supplementation; fibrogenesis; genetic makeup; genetic variant; in vivo; interest; knock-down; knockout gene; molecular marker; mortality; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; personalized medicine; personalized therapeutic; predicting response; predictive marker; public health relevance; response; saturated fat; success; treatment planning; treatment strategy

 DESCRIPTION (provided by applicant): The long-term goal of our research is to reveal mechanisms underlying the naturally existing genetic variation of human fatty acid desaturase 1 (FADS1) gene in increasing the risk for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH); and to establish an evidence-based, personalized treatment strategy for NAFLD and NASH, with omega-3 (n-3) polyunsaturated fatty acids (PUFA) as a safe and inexpensive medication. The immediate goal of this application is to investigate the causal role of genetic variation of human fatty acid desaturase 1 (FADS1) gene in the development of NAFLD and NASH and in the response to n-3 PUFA supplementation in NAFLD. NAFLD and NASH are common chronic liver diseases causing significant morbidity and mortality, but with very limited treatment options. Many studies to date have demonstrated that n-3 PUFA deficiency is a risk factor for NAFLD. The levels of n-3 PUFAs in the blood and liver of NAFLD patients are significantly lower than in healthy individuals, and beneficial effects of n- PUFA supplementation in these patients have been increasingly recognized. However, recent clinical trials using n-3 PUFA to treat NAFLD yield mixed results, and this could be due to inter-patient difference in response to n-3 PUFA. Numerous studies have consistently demonstrated that blood n-3 PUFA levels in human population are significantly influenced by genetic variants in the FADS1 gene which encodes a key enzyme for converting dietary n-3 lipids into bioactive forms such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Individuals carrying the low-function alleles (>33% among major populations) of these variants have a much lower blood EPA and DHA levels than those with normal function alleles. Our recent studies demonstrated that these alleles markedly reduce FADS1 activity in human livers, leading to accumulation of saturated lipids and total fat, which also significantly increase the rik for NASH. We thus hypothesize that reduced FADS1 function increases the risk for NAFLD and NASH, and at the same time also increases an individual's sensitivity to n-3 PUFA treatment for NAFLD. We have performed preliminary studies in cell lines and have also established a murine model with Fads1 gene knockout. Our newly collected data with these models strongly support our hypotheses. In the current application, we propose to continue our success to focus on: 1) To establish the causal role and elucidate the mechanism of reduced FADS1 function in increasing the risk for NAFLD; 2) To test hypothesis that reduced FADS1 function leads to increased sensitivity to n-3 PUFA in ameliorating NAFLD; and 3) To validate the two relationships mentioned above in human NAFLD samples and primary hepatocytes. Our study will fill key knowledge gaps in this area and will provide important data needed to design and conduct genotype-stratified strategy for dietary or therapeutic or preventive intake of n-3 PUFA in treating NAFLD and beyond.

 描述（申请人提供）：我们研究的长期目标是揭示人类脂肪酸去饱和酶1（FADS 1）基因天然存在的遗传变异增加非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）风险的机制;并为NAFLD和NASH建立基于证据的个性化治疗策略，将omega-3（n-3）多不饱和脂肪酸（PUFA）作为安全廉价的药物。本申请的直接目标是研究人脂肪酸去饱和酶1（FADS 1）基因的遗传变异在NAFLD和NASH的发展中以及在NAFLD中对n-3 PUFA补充的响应中的因果作用。NAFLD和NASH是常见的慢性肝病，导致显著的发病率和死亡率，但治疗选择非常有限。迄今为止，许多研究表明，n-3 PUFA缺乏是NAFLD的危险因素。NAFLD患者的血液和肝脏中的n-3 PUFA水平显著低于健康个体，并且这些患者中n-PUFA补充的有益效果已经越来越被认识到。然而，最近使用n-3 PUFA治疗NAFLD的临床试验产生了混合的结果，这可能是由于患者对n-3 PUFA的反应存在差异。大量研究一致表明，人类血液中的n-3 PUFA水平受到FADS 1基因的遗传变异的显著影响，FADS 1基因编码将膳食n-3脂质转化为生物活性形式如二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的关键酶。携带这些变体的低功能等位基因（在主要人群中>33%）的个体的血液EPA和DHA水平比具有正常功能等位基因的个体低得多。我们最近的研究表明，这些等位基因显著降低了人类肝脏中的FADS 1活性，导致饱和脂质和总脂肪的积累，这也显著增加了NASH的风险。因此，我们假设FADS 1功能降低会增加NAFLD和NASH的风险，同时也会增加个体对NAFLD的n-3 PUFA治疗的敏感性。我们已经在细胞系中进行了初步研究，并建立了Fads 1基因敲除的小鼠模型。我们用这些模型新收集的数据有力地支持了我们的假设。在本申请中，我们建议继续我们的成功，以专注于：1）建立因果关系并阐明FADS 1功能降低在增加NAFLD风险中的机制; 2）检验FADS 1功能降低导致改善NAFLD中对n-3 PUFA敏感性增加的假设;和3）在人NAFLD样品和原代肝细胞中验证上述两种关系。我们的研究将填补这一领域的关键知识空白，并将提供设计和实施基因型分层策略所需的重要数据，用于治疗NAFLD及其他疾病的饮食或治疗或预防性摄入n-3 PUFA。