Non-alcoholic fatty liver disease (NAFLD) is a growing health problem worldwide, ranging from non-alcoholic fatty liver (NAFL) to the more severe metabolic non-alcoholic steatohepatitis (NASH). Although many studies have elucidated the pathogenesis of NAFLD, the epigenetic regulatory mechanism from NAFL to NASH remains incompletely understood. The histone H3 lysine 4 methyltransferase, MLL4 (also called KMT2D), is a critical epigenetic transcriptional coactivator that mediates overnutrition-induced steatosis in mice, but its potential role in the progression of NASH remains largely unknown. Here, we show that mice lacking the one allele of the Mll4 gene are resistant to hepatic steatosis, inflammation, and fibrosis in NASH conditions compared to wild-type controls. Transcriptome analysis of the livers of control and Mll4+/- mice identified pro-inflammatory genes regulated by the nuclear factor kappa B (NF-κB) signaling pathway as major target genes of MLL4. We show that MLL4 binds to p65 and that MLL4 is required for NF-κB transactivation. Myeloid-specific Mll4 knockout mice showed an almost complete block of NASH, while hepatocyte-specific Mll4 knockout mice showed mild inhibition of steatosis. Pro-inflammatory M1 polarization is decreased and anti-inflammatory M2 polarization is increased in liver macrophages from myeloid-specific Mll4 knockout mice. Importantly, we show that histone H3-lysine 4 methylation mediated by the MLL4-complex plays a critical role in promoting the expression of Ccl2 in hepatocytes and M1 marker genes in macrophages. Our results demonstrate that MLL4, through the NF-κB-MLL4 regulatory axis, exacerbates steatohepatitis in the context of an inflammatory response and represents a potential therapeutic target for NASH.

中文翻译：

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甲基转移酶 MLL4 通过增强 NF-κB 信号传导促进非酒精性脂肪性肝炎。


非酒精性脂肪性肝病 （NAFLD） 是世界范围内日益严重的健康问题，从非酒精性脂肪肝 （NAFL） 到更严重的代谢性非酒精性脂肪性肝炎 （NASH）。尽管许多研究已经阐明了 NAFLD 的发病机制，但从 NAFL 到 NASH 的表观遗传调控机制仍不完全清楚。组蛋白 H3 赖氨酸 4 甲基转移酶 MLL4 （也称为 KMT2D） 是一种关键的表观遗传转录共激活因子，可介导营养过剩诱导的小鼠脂肪变性，但其在 NASH 进展中的潜在作用在很大程度上仍是未知的。在这里，我们表明，与野生型对照相比，缺乏 Mll4 基因的一个等位基因的小鼠在 NASH 条件下对肝脂肪变性、炎症和纤维化具有抵抗力。对照小鼠和 Mll4+/- 小鼠肝脏的转录组分析发现，受核因子 kappa B （NF-κB） 信号通路调控的促炎基因是 MLL4 的主要靶基因。我们表明 MLL4 与 p65 结合，并且 MLL4 是 NF-κB 反式激活所必需的。髓系特异性 Mll4 敲除小鼠显示几乎完全阻断 NASH，而肝细胞特异性 Mll4 敲除小鼠显示脂肪变性的轻度抑制。来自髓系特异性 Mll4 敲除小鼠的肝脏巨噬细胞中的促炎 M1 极化降低，抗炎 M2 极化增加。重要的是，我们表明由 MLL4 复合物介导的组蛋白 H3-赖氨酸 4 甲基化在促进肝细胞中 Ccl2 和巨噬细胞中 M1 标志基因的表达中起关键作用。我们的结果表明，MLL4 通过 NF-κB-MLL4 调节轴在炎症反应的情况下加剧脂肪性肝炎，并代表了 NASH 的潜在治疗靶点。