不可溶膳食纤维协同基因风险对非酒精性脂肪肝交互作用的机制研究

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased worldwide and dietary changing is one of the primary treatments for NAFLD. Our previous findings have provided evidence that high consumption of dietary pattern which rich in insoluble dietary fiber (IDF) is associated with lower prevalence of NAFLD. Moreover, there is an interaction effect between IDF consumption and genetic risk score (GRS) on NAFLD. Nevertheless, to date, the mechanisms underlying this interaction effect is still unclear. Thus, firstly, we are proposed to investigate whether butyrate, which was generated by gut microbe fermentation of IDF, may interact with IDF and associated with the risk of NAFLD through regulating the expression of NAFLD related risk genes. Meanwhile, we will carry out a prospective cohort study and investigate the interaction effect between IDF dietary pattern and GRS/expression of NAFLD related risk genes on NAFLD. Taken together, the results of the present study will not only contribute to understanding the potential mechanisms of the interaction effect between IDF consumption and NAFLD related GRS on the risk of NAFLD but also provide evidence and support the development of dietary suggestions for NAFLD with different GRS, which has important clinical implication for reducing the disease burden of NAFLD.

非酒精性脂肪肝（NAFLD）发病率不断增高，已经成为一项不容忽视的公共卫生问题。改善饮食被认为是NAFLD防治的有效办法。我们的前期研究中发现，不可溶膳食纤维（IDF）膳食模式与NAFLD患病率呈负相关，且IDF膳食与NAFLD基因风险评分对NAFLD的发生具有交互调控作用，但该交互作用的机制尚不清晰。本课题拟先通过动物体内试验研究IDF被丁酸盐产生菌发酵产生丁酸盐，并进一步通过抑制去乙酰化作用调控NAFLD风险基因表达，继而协同IDF膳食对NAFLD的改善起到交互作用；同时基于人群队列前瞻性研究IDF膳食模式协同基因风险评分及NAFLD相关风险基因蛋白表达水平调控NAFLD的交互作用及其大小。本研究不仅能够为明确IDF膳食调控NAFLD风险基因表达，进而影响NAFLD发生发展的作用机制提供研究证据，且也为不同NAFLD基因风险人群构建特异性防治膳食提供理论基础。

非酒精性脂肪肝（NAFLD）疾病负担不断升高，膳食干预被认为是NAFLD安全有效的干预措施。本课题结合动物实验和人群研究，利用动物实验明确膳食纤维（DF）干预通过影响小鼠肝脏免疫系统、氧化应激和脂质代谢，从而改善NAFLD表型。利用前瞻性自然人群队列研究分析DF摄入与新发NAFLD风险关联，并进一步探讨DF膳食及其代谢产物丁酸盐与NAFLD风险基因对NAFLD发生发展交互作用。.动物研究发现，DF干预增加了肠道微生物群的多样性，通过Acly/Nrf2/NF-κB信号通路降低炎症、氧化应激和脂质合成，同时改善肠道屏障，进而改善NAFLD进展。人群研究发现，摄入较多的IDF与新诊断NAFLD患病率降低相关，摄入全谷物、豆类食物、蔬菜和坚果来源的DF对新诊断NAFLD的患病率有有利影响。此外，本研究随机选取NAFLD患者和健康对照进行粪便菌群和血液基因测序，计算基因风险评分，以待后续进行DF摄入及其代谢产物丁酸盐与基因风险交互作用研究。.本研究明确了DF改善NAFLD的作用机制，为以DF干预途径的NAFLD防治手段开发提供理论依据和实践证据，对从膳食途径防控NAFLD，降低其人群疾病负担具有重要公共卫生意义。