NAD对非酒精性脂肪肝的调节作用及其分子机制研究

Currently, Nonalcoholic fatty liver disease (NAFLD) is becoming an increasing common problem worldwide, while the treatment methods of NAFLD are still very limited. More studies on the pathological mechanism of NAFLD are required to develop new therapeutical method for NAFLD. It has been reported that ethanol can increase the NADH/NAD ratio, which is the main mechanism of alcoholic fatty liver disease. However, the role of NAD in NAFLD has not been clarified yet. In this study, we will explore the relationship between NAD and NAFLD using relevant cell and mouse models; and determine whether inhibition of NAD decline in the cell or mouse can delay the onset of NAFLD by the addition of NAD precursors in the cell culture medium or feed, or by using WldS mice as the mouse model with higher NAD synthesis ability. Moreover, we'd like to screen the enzymes or proteins related to the synthesis or consumptions of NAD and find the key enzymes or proteins that regulate NAD level and modulate the onset of NAFLD. Furthermore, the regulating mechanism of the key enzyme or protein will be investigated. With this research project, we are expecting to find at least one key protein in NAD metabolism which is related with NAFLD. Our study will extend the understanding on NAFLD and provide new potential drug targets for its treatment.

近年来非酒精性脂肪肝的发病率逐年攀升，而其治疗手段却仍非常局限。因此，深入研究非酒精性脂肪肝的发病机制，寻找新的治疗方法至关重要。有报道NAD在脂肪肝发生过程中显著下调，但NAD水平的调节在非酒精性脂肪肝中的作用和机制还有待阐明。本研究拟通过建立非酒精性脂肪肝的细胞和小鼠模型，确定NAD下降与非酒精性脂肪肝的相关性；通过补充NAD前体或利用具有高NAD合成酶活性的WldS小鼠在细胞和小鼠水平研究抑制NAD下降是否可以缓解非酒精性脂肪肝的发生；并进一步通过siRNA在细胞水平筛选NAD合成途径和消耗途径中可以影响肝细胞脂肪积累的基因；对有效的基因在细胞和小鼠水平进一步验证其是否通过调节NAD水平而影响非酒精性脂肪肝的发生，并初步探索其作用的分子机制。本项目的顺利开展，预期至少会找到一个通过调节NAD水平缓解非酒精性脂肪肝的关键基因，从而为深入了解非酒精性脂肪肝的发病机制及其治疗提供新的思路。

近年来非酒精性脂肪肝的发病率逐年攀升，而其治疗手段却仍非常局限。因此，深入研究非酒精性脂肪肝的发病机制，寻找新的治疗方法至关重要。有报道NAD在脂肪肝发生过程中显著下调，但NAD水平的调节在非酒精性脂肪肝中的作用和机制还有待阐明。本研究通过建立非酒精性脂肪肝的细胞模型，确定了NAD下降与非酒精性脂肪肝的相关性；通过补充NAD前体或利用具有高NAD合成酶活性的WldS小鼠的肝脏细胞，在细胞水平上确定了上调NAD水平对非酒精性脂肪肝的缓解作用；并进一步通过Real-time PCR在细胞水平筛选了NAD合成途径和消耗途径中可以影响肝细胞脂肪积累的基因，发现了NMNAT2在非酒精性脂肪肝发病过程中的潜在作用，并成功地构建了NMNAT2条件性基因敲除小鼠模型。同时我们还发现NAD合成在节律调节中的作用，为NAD合成对生物体节律调节作用做了重要的补充。研究结果发表在国际学术期刊Hepatology，总体上完成了本项目。