Huffington Center on Aging and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2013 Mar 28;3(3):831-43. doi: 10.1016/j.celrep.2013.02.009. Epub 2013 Mar 14.
Molecular mechanisms underpinning nonalcoholic fatty liver disease (NAFLD) are not well understood. The earliest step of NAFLD is hepatic steatosis, which is one of the main characteristics of aging liver. Here, we present a molecular scenario of age-related liver steatosis. We show that C/EBPα-S193D knockin mice have age-associated epigenetic changes and develop hepatic steatosis at 2 months of age. The underlying mechanism of the hepatic steatosis in old wild-type (WT) mice and in young S193D mice includes increased amounts of tripartite p300-C/EBPα/β complexes that activate promoters of five genes that drive triglyceride synthesis. Knockdown of p300 in old WT mice inhibits hepatic steatosis. Indeed, transgenic mice expressing dominant-negative p300 have fewer C/EBPα/β-p300 complexes and do not develop age-dependent hepatic steatosis. Notably, the p300-C/EBPα/β pathway is activated in the livers of patients with NAFLD. Thus, our results show that p300 and C/EBP proteins are essential participants in hepatic steatosis.
非酒精性脂肪性肝病（NAFLD）的分子机制尚不清楚。NAFLD 的最早阶段是肝脂肪变性，这是衰老肝脏的主要特征之一。在这里，我们提出了一个与年龄相关的肝脂肪变性的分子情景。我们表明，C/EBPα-S193D 基因敲入小鼠具有与年龄相关的表观遗传变化，并在 2 月龄时发展为肝脂肪变性。老年野生型（WT）小鼠和年轻 S193D 小鼠中肝脂肪变性的潜在机制包括三部分 p300-C/EBPα/β 复合物的含量增加，这些复合物激活了五个驱动甘油三酯合成的基因的启动子。在老年 WT 小鼠中敲低 p300 可抑制肝脂肪变性。事实上，表达显性负 p300 的转基因小鼠中 C/EBPα/β-p300 复合物较少，不会发生年龄依赖性肝脂肪变性。值得注意的是，p300-C/EBPα/β 通路在 NAFLD 患者的肝脏中被激活。因此，我们的研究结果表明，p300 和 C/EBP 蛋白是肝脂肪变性的重要参与者。
