PPARα调控lncENAF影响肝脏胆固醇代谢的分子机制及其在NASH形成中的作用

在前期研究中，我们发现一条lncRNA在小鼠脂肪肝中表达增高，命名为lncENAF。LncENAF在肝脏中特异表达，定位在细胞核内，可被PPARα激动剂激活，并影响胆固醇合成基因如Fdft1的表达、HMG-CoA酶活性和细胞内胆固醇的水平。我们鉴定出了lncENAF可以结合hnRNPF，敲低hnRNPF，同样可影响胆固醇代谢。我们提出一条新的胆固醇代谢调节通路：PPARα—lncENAF /hnRNPF—Fdft1，lncENAF可能是连接PPARα和胆固醇合成代谢的桥梁。脂肪肝中脂肪酸可激活PPARα，上调lncENAF，lncENAF/hnRNPF与胆固醇合成基因的启动子结合并抑制表达，从而稳定细胞内胆固醇含量，减轻脂毒性，阻止或减缓NASH的进展。本研究通过ChIP、基因敲除小鼠等技术研究lncENAF对胆固醇代谢及对NASH形成的影响，为NAFLD/NASH的诊断和治疗提供新靶点。

In the previous work, we have identified one lncRNA upregulated in fatty liver in mice, which was named lncENAF (Elevated in Non Alcoholic Fatty Liver). LncENAF was expressed in liver in a tissue-specific pattern, and predominantly localized in nucleus. LncENAF was activated by PPARα agonists and resulted in the suppression of genes related to cholesterol synthesis such as Fdft1 as well as the activity of HMG-CoA reductase and intracellular cholesterol levels. We have identified lncENAF interacting with hnRNPF. With the knockdown of hnRNPF, the cholesterol metabolism was changed similar to the lncENAF silencing. We proposed a new pathway regulating cholesterol metabolism: PPARα-lncENAF/hnRNPF-Fdft1, in which lncENAF might be a mediator linking PPARα and cholesterol anabolism. Fatty acids existing in fatty liver could activate PPARα, subsequently up-regulating lncENAF, and the complex of lncENAF/hnRNPF bond to the promoter of cholesterol synthesis gene and inhibited their expression, which thereby stabilized intracellular cholesterol levels, leading to reduce lipotoxicity and prevent or decelarate the progression of NASH. In this study, the effects of lncENAF on cholesterol metabolism and the development of NASH were investigate via ChIP and knockout mice etc, which will provide novel insight for the diagnosis and treatment of NAFLD/NASH.