Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of liver function and a tumor suppressor in hepatocellular carcinoma (HCC). In this study, we explore the reciprocal negative regulation of HNF4α and cyclin D1, a key cell cycle protein in the liver. Transcriptomic analysis of cultured hepatocyte and HCC cells found that cyclin D1 knockdown induced the expression of a large network of HNF4α-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4α to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4α deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4α maintains proliferative quiescence in the liver, at least, in part, via repression of cyclin D1. Acute cyclin D1 deletion in the regenerating liver markedly inhibited hepatocyte proliferation after partial hepatectomy, confirming its pivotal role in cell cycle progression in this in vivo model, and enhanced the expression of HNF4α target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4α-dependent fashion), indicating that the cyclin D1-HNF4α axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4α was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4α coordinately controls the cell cycle machinery and metabolism in the liver.

肝细胞核因子 4α (HNF4α) 是肝功能的主要调节因子，也是肝细胞癌 (HCC) 中的肿瘤抑制因子。在这项研究中，我们探讨了 HNF4α 和细胞周期蛋白 D1 的相互负调节，细胞周期蛋白是肝脏中的关键细胞周期蛋白。培养的肝细胞和 HCC 细胞的转录组学分析发现，cyclin D1 敲低诱导了 HNF4α 调节基因的大型网络的表达。染色质免疫沉淀测序 (ChIP-seq) 表明，cyclin D1 抑制 HNF4α 与肝脏中数千个靶标的结合，从而减少调节多种代谢活动的相关基因的表达。相反，肝脏中的急性 HNF4α 缺失会诱导细胞周期蛋白 D1 和肝细胞周期进程；同步细胞周期蛋白 D1 消融阻断了这种增殖，表明 HNF4α 至少部分地通过抑制细胞周期蛋白 D1 在肝脏中维持增殖静止。再生肝脏中的急性cyclin D1缺失显着抑制部分肝切除术后肝细胞增殖，证实了其在该体内模型中的细胞周期进程中的关键作用，并增强了HNF4α靶蛋白的表达。肝细胞cyclin D1基因消融导致餐后肝糖原水平显着增加（以HNF4α依赖性方式），表明cyclin D1-HNF4α轴调节葡萄糖代谢以响应进食。在 AML12 肝细胞中，cyclin D1 耗竭导致葡萄糖摄取增加，如果 HNF4α 同时耗竭，这种情况就会被否定，并显着提高糖原合成。总结一下，