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

 描述(由申请人提供)：我们研究的长期目标是揭示人类脂肪酸去饱和酶1(FADS1)基因自然存在的遗传变异在增加患非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)风险方面的潜在机制；并建立一种基于证据的、个性化的治疗NAFLD和NASH的策略，将omega-3(n-3)多不饱和脂肪酸(PUFA)作为一种安全和廉价的药物。本研究的近期目标是研究人类脂肪酸去饱和酶1(FADS1)基因的遗传变异在NAFLD和NASH的发生发展中的作用以及在NAFLD对n-3PUFA补充的反应中的作用。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。到目前为止，许多研究已经证明n-3多不饱和脂肪酸缺乏是NAFLD的危险因素。NAFLD患者血液和肝脏中的n-3PUFAs水平明显低于健康人，补充n-PUFA对这些患者的益处日益得到认可。然而，最近使用n-3PUFA治疗NAFLD的临床试验结果喜忧参半，这可能是由于患者对n-3PUFA的反应不同所致。大量研究表明，人类血液中n-3多不饱和脂肪酸水平受到FADS1基因遗传变异的显著影响，FADS1基因编码一种关键酶，用于将饮食中的n-3脂肪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)。携带这些变异的低功能等位基因的个体(主要人群中有33%)与那些具有正常功能等位基因的个体相比，血液中的EPA和DHA水平要低得多。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FADS1的活性，导致饱和脂肪和总脂肪的积累，这也显著增加了NASH的风险。因此，我们假设FADS1功能降低增加了NAFLD和NASH的风险，同时也增加了个体对n-3PUFA治疗NAFLD的敏感性。我们已经在细胞系中进行了初步研究，并建立了Fads1基因敲除的小鼠模型。我们用这些模型收集的新数据有力地支持了我们的假设。在目前的应用中，我们建议继续我们的成功，专注于：1)确定FADS1功能降低在增加NAFLD风险中的因果作用并阐明其机制；2)检验FADS1功能降低导致对n-3多不饱和脂肪酸敏感性增加的假设，以改善NAFLD；以及3)在人NAFLD样本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，并将为设计和实施n-3多不饱和脂肪酸在治疗NAFLD及以后的饮食或治疗性或预防性摄入n-3 PUFA的基因分层策略提供重要数据。

 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.