非酒精性脂肪肝风险基因SIRT3变异和膳食能量摄入水平对肝脏脂肪积累的交互影响和机理研究

Non-alcoholic fatty liver disease (NAFLD) is one of the major public health challenges worldwide, with its prevalence increasing rapidly in recent years. High dietary intake is a risk factor of NAFLD. It has been demonstrated that high fat diet intervention can decrease the expression of Sirt3, and subsequently induce the dysfunction of lipid metabolism in liver cells. Our previous case-control study has suggested that SIRT3 gene variants rs11246020 and r12226697 is associated with NAFLD risk and their OR changes between cohorts with different dietary energy intake. Based on the above evidences, we propose that SIRT3 gene polymorphisms may interact with diet energy intake in modulating fat accumulation in liver cells. This project is designed to acquire more genotyping and dietary energy intake data in a bigger cohort to verify the gene-diet interaction model we found in our previous study. And we also try to find out how would the liver fat accumulation state of SIRT3 gene knockout mice change in different energy intake and with different SIRT3 variants expressing in their liver cells. This research will help to make personalized nutritional intervention plan for NAFLD prevention in the future.

非酒精性脂肪性肝病（NAFLD）发病率逐年升高，因其前期危害不显著易被人们忽视，但长期慢性发展可造成严重后果。高膳食能量摄入是NAFLD的风险因素，能量摄入水平可调节线粒体去乙酰化酶SIRT3表达进而影响肝脏细胞脂肪酸氧化。我们前期的病例-对照研究发现SIRT3基因变异rs11246020、rs12226697与NAFLD风险相关，且风险程度受能量摄入水平影响。既往体外研究证实编码区错义突变rs11246020影响SIRT3去乙酰化酶活性。基于上述线索我们假设：SIRT3不同基因型个体对能量摄入水平变化存在差异性应答，并最终影响肝脏脂肪积累。计划通过扩大人群研究验证SIRT3基因中NAFLD风险变异与膳食能量的交互影响，同时构建不同SIRT3突变体，在SIRT3基因敲除小鼠模型上证实不同突变体和膳食能量摄入不同水平对肝脏脂肪积累的交互作用模式及机理，为个性化的NAFLD膳食指导提供依据。

非酒精性脂肪性肝病（NAFLD）在全世界范围内发病率持续攀升，当前防控是主要策略。随着测序、芯片技术的发展，遗传诊断能够为个体慢病防控提供依据，但慢病的基因-环境（尤其是膳食）互作的复杂性导致慢病的遗传风险评估大多数停留在风险数据的表面，更精细的个体化的疾病防控措施缺失。本研究以NAFLD人群研究为出发点，旨在建立相当规模的病例对照研究队列，并收集以膳食摄入为主的环境因素数据结合靶向SIRT3基因组标记物分型数据开展多模型统计分析发现基因-坏境交互在NAFLD发生中的作用模式。为NAFLD的精准化、个体化防控提供有效数据支撑。由于SIRT3在代谢调节、能量感知等重要生物学过程中的作用，本研究还计划在动物水平开展功能验证以期挖掘深层次的机理。本研究发现和确证了SIRT3基因的rs11246020， rs73392700与我国西南地区NAFLD发生风险相关；膳食营养与基因型交互分析发现rs11246020与能量摄入、 rs73392700与蛋白摄入在NAFLD发生风险中存在交互影响；虽然基因敲除小鼠平台实验显示出阴性结果，但也在动物模型上证实过表达SIRT3可以有效缓解HFD诱导的肥胖和NALFD及相关代谢综合症指标；此外，动物水平研究还发现SIRT3在体内发挥作用受到小鼠能量摄入（高脂膳食、普通膳食）的影响下，低能量摄入水平下，过度表达或激活SIRT3 可能起到脂肪积累增加等负面调节作用。细胞水平研究发现SIRT3可能通过影响线粒体蛋白乙酰化调节脂肪积累和NAFLD发生风险。本研究结果能为NAFLD的基因-营养风险预警和个性化膳食营养调整提供策略和指导。