CREBH通过调控SIRT3/脂肪酸氧化通路酶对非酒精性脂肪性肝病的影响及机制

cAMP-responsive element-binding protein H (CREBH) is a liver-enriched transcription factor and plays a critical role in the regulation of lipid metabolism. However, the molecular mechanism of CREBH in non-alcoholic fatty liver disease (NAFLD) is still not clear. In the preliminary work, we found that lipid droplet deposition in liver tissue of NAFLD animal model treated with CREBH adeno-associated virus were significantly alleviated. By integrating promoter sequences, transcriptome databases and preliminary experimental results, we found that CREBH was most likely to ameliorate hepatic lipid accumulation and progression in NAFLD through regulating the expression of sirtuin 3(SIRT3) and increasing the deacetylation levels of fatty acid oxidation related enzymes. Therefore, this project is to investigate the role and molecular mechanisms of CREBH in cell and animal models of NAFLD using hepatic-specific CREBH knockout mice model, virus transfection, chromatin immunoprecipitation and other molecular biology technologies. Our project may provide new theoretical and experimental basis for blocking the occurrence and progression of NAFLD.

环磷酸腺苷反应元件结合蛋白H（CREBH）为肝富集转录因子，参与调节肝内脂质代谢，但其在非酒精性脂肪性肝病（NAFLD）中的作用机制尚不清楚。我们课题组在前期工作中发现上调CREBH表达能使NAFLD小鼠肝组织中脂滴沉积显著减轻。综合启动子序列，转录组数据库和预实验结果提示，该蛋白极可能是通过转录调节肝内线粒体能量感受器沉默调节蛋白3（SIRT3）的表达，增加脂肪酸氧化通路酶的去乙酰化活性，改善NAFLD的发生与发展。因此，本课题以CREBH作为切入点，选用NAFLD细胞和动物模型，利用条件性基因敲除小鼠、病毒感染和染色质免疫共沉淀等分子生物学技术，明确CREBH在NAFLD肝脂代谢中的重要作用及其机制，为阻断NAFLD的发生与发展提供新的理论和实验依据。

环磷酸腺苷反应元件结合蛋白H(CREBH)为肝富集转录因子，参与调节肝内脂质代谢及炎症反应，但其在非酒精性脂肪性肝病(NAFLD)中的作用机制尚不清楚。本课题发现并证实了CREBH通过正向调节肝内线粒体能量感受器沉默调节蛋白3(SIRT3)，促使SIRT3表达和活化，加速SIRT3对参与脂肪酸氧化(FAO)通路的酶进行脱乙酰化修饰，降低长链酰基辅酶A脱氢酶(ACADL)和肉碱棕榈酰基转移酶2(CPT2)的乙酰化，恢复肝细胞内脂质FAO依赖性分解代谢，减轻NAFLD肝组织中脂质蓄积；同时，CREBH通过调控SIRT3的表达来调节锰超氧化物歧化酶(MnSOD)的赖氨酸乙酰化水平和活性状态，MnSOD的活性增强，从而减轻肝细胞内线粒体氧化应激，达到抑制肝细胞内炎症反应甚至纤维化形成的目的。因此，本课题以CREBH作为切入点，选用NAFLD细胞和动物模型，利用基因敲除小鼠、病毒感染和染色质免疫共沉淀等分子生物学技术，明确了CREBH在NAFLD肝脂代谢和线粒体氧化应激中的重要作用及其机制，为阻断NAFLD的发生与发展提供新的理论和实验依据。