Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4α.
Cyclin D1 inhibits hepatic lipogenesis via repression of carbohydrate response element binding protein and hepatocyte nuclear factor 4α.
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DOI：
10.4161/cc.21019
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发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Albrecht JH
中科院分区：
文献类型：
--
作者：
Hanse EA;Mashek DG;Becker JR;Solmonson AD;Mullany LK;Mashek MT;Towle HC;Chau AT;Albrecht JH
急性肝损伤后，肝脏的代谢能力在代偿性肝细胞增殖过程中发生改变，机制尚不明确。在这项研究中，我们研究了细胞周期蛋白D1对新生脂肪形成的调节，细胞周期蛋白D1是肝细胞周期进程的关键介质。在原代肝细胞中，细胞周期蛋白D1在葡萄糖刺激下显著损害脂肪生成。Cyclin D1抑制葡萄糖介导的关键脂肪生成基因的诱导，并且使用不激活cdk4或诱导细胞周期进展的突变体（D1- ke）可以观察到类似的效果。Cyclin D1（而不是D1- ke）通过调节碳水化合物反应元件结合蛋白（ChREBP）的葡萄糖感应基序来抑制该转录因子的活性。由于ChREBP活性的变化不能完全解释cyclin D1的作用，我们研究了肝细胞核因子4α (HNF4α)，它调节肝脏的许多分化功能，包括脂质代谢。我们发现细胞周期蛋白D1和D1- ke都与HNF4α结合，并显著抑制其在肝细胞中募集到脂肪生成基因的启动子区域。相反，在AML12肝细胞系中，cyclin D1的下调促进了HNF4α活性和脂肪生成。在小鼠肝脏中，HNF4α与细胞周期蛋白D1的中心结构域结合，参与转录抑制。碳水化合物喂养后，Cyclin D1抑制肝脏脂肪生成基因的表达。在再生肝中生理性cyclin D1表达的情况下也观察到类似的结果。综上所述，这些研究表明cyclin D1通过cdk4依赖性和非依赖性机制抑制肝细胞中的ChREBP和HNF4α功能。这些发现提供了细胞周期机制和肝脏代谢功能的转录控制之间的直接联系。
Following acute hepatic injury, the metabolic capacity of the liver is altered during the process of compensatory hepatocyte proliferation by undefined mechanisms. In this study, we examined the regulation of de novo lipogenesis by cyclin D1, a key mediator of hepatocyte cell cycle progression. In primary hepatocytes, cyclin D1 significantly impaired lipogenesis in response to glucose stimulation. Cyclin D1 inhibited the glucose-mediated induction of key lipogenic genes, and similar effects were seen using a mutant (D1-KE) that does not activate cdk4 or induce cell cycle progression. Cyclin D1 (but not D1-KE) inhibited the activity of the carbohydrate response element-binding protein (ChREBP) by regulating the glucose-sensing motif of this transcription factor. Because changes in ChREBP activity could not fully explain the effect of cyclin D1, we examined hepatocyte nuclear factor 4α (HNF4α), which regulates numerous differentiated functions in the liver including lipid metabolism. We found that both cyclins D1 and D1-KE bound to HNF4α and significantly inhibited its recruitment to the promoter region of lipogenic genes in hepatocytes. Conversely, knockdown of cyclin D1 in the AML12 hepatocyte cell line promoted HNF4α activity and lipogenesis. In mouse liver, HNF4α bound to a central domain of cyclin D1 involved in transcriptional repression. Cyclin D1 inhibited lipogenic gene expression in the liver following carbohydrate feeding. Similar findings were observed in the setting of physiologic cyclin D1 expression in the regenerating liver. In conclusion, these studies demonstrate that cyclin D1 represses ChREBP and HNF4α function in hepatocytes via Cdk4-dependent and -independent mechanisms. These findings provide a direct link between the cell cycle machinery and the transcriptional control of metabolic function of the liver.
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