Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Medicine, University of Southern California, Los Angeles, California, USA.
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
J Biol Chem. 2021 Jan-Jun;296:100235. doi: 10.1074/jbc.RA120.016079. Epub 2021 Jan 7.
Epigenetic mechanisms that alter heritable gene expression and chromatin structure play an essential role in many biological processes, including liver function. Human MOF (males absent on the first) is a histone acetyltransferase that is globally downregulated in human steatohepatitis. However, the function of MOF in the liver remains unclear. Here, we report that MOF plays an essential role in adult liver. Genetic deletion of Mof by Mx1-Cre in the liver leads to acute liver injury, with increase of lipid deposition and fibrosis akin to human steatohepatitis. Surprisingly, hepatocyte-specific Mof deletion had no overt liver abnormality. Using the in vitro coculturing experiment, we show that Mof deletion-induced liver injury requires coordinated changes and reciprocal signaling between hepatocytes and Kupffer cells, which enables feedforward regulation to augment inflammation and apoptotic responses. At the molecular level, Mof deletion induced characteristic changes in metabolic gene programs, which bore noticeable similarity to the molecular signature of human steatohepatitis. Simultaneous deletion of Mof in both hepatocytes and macrophages results in enhanced expression of inflammatory genes and NO signaling in vitro. These changes, in turn, lead to apoptosis of hepatocytes and lipotoxicity. Our work highlights the importance of histone acetyltransferase MOF in maintaining metabolic liver homeostasis and sheds light on the epigenetic dysregulation in liver pathogenesis.
表观遗传机制改变可遗传的基因表达和染色质结构，在许多生物学过程中发挥着重要作用，包括肝功能。人类 MOF（雄性缺失第一个）是一种组蛋白乙酰转移酶，在人类脂肪性肝炎中全局下调。然而，MOF 在肝脏中的功能尚不清楚。在这里，我们报告 MOF 在成年肝脏中发挥着重要作用。在肝脏中通过 Mx1-Cre 进行的 Mof 基因缺失会导致急性肝损伤，脂质沉积增加和纤维化类似于人类脂肪性肝炎。令人惊讶的是，肝细胞特异性 Mof 缺失没有明显的肝脏异常。通过体外共培养实验，我们表明 Mof 缺失诱导的肝损伤需要肝细胞和库普弗细胞之间的协调变化和相互信号传递，从而实现正向调节以增强炎症和凋亡反应。在分子水平上，Mof 缺失诱导代谢基因程序的特征变化，与人类脂肪性肝炎的分子特征具有明显的相似性。同时在肝细胞和巨噬细胞中缺失 Mof 会导致体外炎症基因和 NO 信号的表达增强。这些变化反过来又导致肝细胞凋亡和脂肪毒性。我们的工作强调了组蛋白乙酰转移酶 MOF 在维持代谢性肝稳态中的重要性，并揭示了肝发病机制中的表观遗传失调。
