PNPLA7蛋白调控肝脏脂肪代谢和非酒精性脂肪肝病的作用和分子机制

The metabolic syndrome caused by imbalance of body energy metabolism greatly harm human health. The Non-Alcoholic fatty liver disease （NAFLD） is the liver manifestation and clinical feature of metabolic syndrome. The neutral lipid especially triglyceride accumulated in liver of NAFLD patient in the absence of excessive alcohol consumption, viral infection and other specific reasons. The occurrence of NAFLD associated with not only impaired metabolic process but also genetic predisposition and environmental factor. PNPLA7 is the unknown function lipid droplets associate protein which highly expressed in liver and adipose tissue. The preliminary results of our study show that overexpress PNPLA7 in liver reduces high fat diet induced hepatic lipid accumulation which indicating that PNPLA7 protein plays an important regulatory role in the occurrence of NAFLD and hepatic lipid metabolism . In this project, we will ob/ob mouse and establish PNPLA7 liver specific transgenic mouse as model system to investigate the physiological role of PNPLA7 in regulating hepatic lipid metabolism and find interacting protein of PNPLA7 in liver.We will use biochemstry and molecular biology technique to reveal the physiological function and molecular mechanism of PNPLA7 on hepatic lipid metabolism and NAFLD,thus provide new insight of regulatory network of NAFLD and new target for prevention and treatment of NAFLD and metabolic syndrome.

由于机体能量代谢失调导致的代谢综合征极大的危害了人类健康。非酒精性脂肪肝病（NAFLD）是代谢综合征的一个肝脏表现和临床特点。在无过量饮酒史，病毒感染及其他特殊原因时，中性脂肪尤其是甘油三酯在肝脏中堆积是NAFLD的主要特征。NAFLD的发生和肝脏内的很多代谢途径相关，同时又和遗传性的易患病体质和环境因素有关。PNPLA7蛋白是一种未知功能的脂滴蛋白，在肝脏、脂肪组织和肌肉中表达。通过前期研究我们发现在肝脏过表达PNPLA7蛋白可以拮抗高脂饮食导致的肝脏脂肪堆积，显示PNPLA7蛋白在NAFLD的发生以及肝脏脂类新陈代谢调控中发挥着重要作用。我们拟通过使用ob/ob小鼠和建立肝脏PNPLA7转基因小鼠，探讨PNPLA7蛋白在肝脏的生理功能，同时寻找与PNPLA7相互作用蛋白，结合体内外实验确定PNPLA7调控肝脏脂肪代谢 和NAFLD的作用及分子机制，给NAFLD的治疗和预防提供新的靶点。

由于机体能量代谢失调导致的代谢综合征极大的危害了人类健康。非酒精性脂肪肝病（NAFLD）是代谢综合征的一个肝脏表现和临床特点。NAFLD的发生和肝脏内的很多代谢途径相关，同时又和遗传性的易患病体质和环境因素有关。PNPLA7蛋白是一种未知功能的脂滴蛋白，在肝脏、脂肪组织和肌肉中表达。通过前期研究我们发现在肝脏过表达PNPLA7蛋白可以拮抗高脂饮食导致的肝脏脂肪堆积，显示PNPLA7蛋白在NAFLD的发生以及肝脏脂类新陈代谢调控中发挥着重要作用。但是PNPLA7在肝脏中如何调控肝脏的脂肪代谢的作用和具体机制还不清楚。本课题通过使用腺病毒在db/db小鼠和正常小鼠肝脏中特异性敲降PNPLA7蛋白，具体探讨了PNPLA7蛋白在肝脏的生理功能，同时寻找与PNPLA7相互作用蛋白，结合体内外实验确定PNPLA7调控肝脏脂肪代谢 和NAFLD的作用及分子机制，给NAFLD的治疗和预防提供新的靶点。我们发现1）通过检测脂肪肝病人的肝脏样本，我们发现PNPLA7 mRNA在脂肪肝病人中的表达水平和正常人相比较是显著升高，并且PNPLA7在肝脏肝病人中的表达水平是和血液中TAG水平呈正相关。2）通过腺病毒在肝脏中敲降PNPLA7后会导致肝脏中脂肪的堆积，而这种脂肪的堆积是由于肝脏VLDL的分泌障碍所引起的。3）经过进一步的研究，我们发现PNPLA7蛋白可以调节内质网相关E3连接酶HARD1导致的APOE蛋白降解，调控肝脏VLDL的分泌。为肝脏脂代谢及NAFLD的防治提供了新的理论依据及靶蛋白。