Biozentrum, University of Basel, 4056, Basel, Switzerland.
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Sci Rep. 2022 Jul 7;12(1):11477. doi: 10.1038/s41598-022-15731-4.
Non-alcoholic fatty liver disease is a continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. The main aim of this study was to dissect transcriptional mechanisms regulated by lipotoxicity in hepatocytes. We achieved this aim by combining transcriptomic, proteomic and chromatin accessibility analyses from human liver and mouse hepatocytes. This integrative approach revealed several transcription factor networks deregulated by NASH and lipotoxicity. To validate these predictions, genetic deletion of the transcription factors MAFK and TCF4 was performed, resulting in hepatocytes that were better protected against saturated fatty acid oversupply. MAFK- and TCF4-regulated gene expression profiles suggest a mitigating effect against cell stress, while promoting cell survival and growth. Moreover, in the context of lipotoxicity, some MAFK and TCF4 target genes were to the corresponding differentially regulated transcripts in human liver fibrosis. Collectively, our findings comprehensively profile the transcriptional response to lipotoxicity in hepatocytes, revealing new molecular insights and providing a valuable resource for future endeavours to tackle the molecular mechanisms of NASH.
非酒精性脂肪性肝病是一种疾病谱，其中非酒精性脂肪性肝炎（NASH）尤其与不良预后相关。肝细胞脂肪毒性是肝纤维化和 NASH 的主要致病因素之一。然而，调节这一过程的分子机制尚不清楚。本研究的主要目的是剖析肝细胞脂肪毒性调节的转录机制。我们通过对人肝和鼠肝细胞的转录组、蛋白质组和染色质可及性分析来实现这一目标。这种综合方法揭示了 NASH 和脂肪毒性失调的几个转录因子网络。为了验证这些预测，我们对转录因子 MAFK 和 TCF4 进行了基因缺失，结果发现这些细胞对饱和脂肪酸供应过剩有更好的保护作用。MAFK 和 TCF4 调节的基因表达谱表明它们具有减轻细胞应激的作用，同时促进细胞存活和生长。此外，在脂肪毒性的情况下，一些 MAFK 和 TCF4 的靶基因与人类肝纤维化中相应的差异调节转录物相对应。总之，我们的研究结果全面描绘了肝细胞对脂肪毒性的转录反应，揭示了新的分子见解，并为未来解决 NASH 的分子机制提供了有价值的资源。
