Liver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and VLDL secretion. In this study, we discovered that KLF2, a transcription factor, plays a crucial role in regulating lipid metabolism in the liver. Overexpression of KLF2 in the liver of db/db mice, C57BL/6J mice, and CD36-/- mice fed on a normal diet resulted in increased lipid content in the liver. Additionally, transgenic mice (ALB-Klf2) that overexpressed KLF2 in the liver developed liver steatosis after being fed a normal diet. We found that KLF2 promotes lipogenesis by increasing the expression of SCAP, a chaperone that facilitates the activation of SREBP, the master transcription factor for lipogenic gene expression. Our mechanism studies revealed that KLF2 enhances lipogenesis in the liver by binding to the promoter of SCAP and increasing the expression of genes involved in fatty acid synthesis. Reduction of KLF2 expression led to a decrease in SCAP expression and a reduction in the expression of SREBP1 target genes involved in lipogenesis. Overexpression of KLF2 also increased the activation of SREBP2 and the mRNA levels of its downstream target SOAT1. In C57BL/6J mice fed a high-fat diet, overexpression of KLF2 increased blood VLDL secretion, while reducing its expression decreased blood cholesterol levels. Our study emphasizes the novelty that hepatic KLF2 plays a critical role in regulating lipid metabolism through the KLF2/SCAP/SREBPs pathway, which is essential for hepatic lipogenesis and maintaining blood cholesterol homeostasis.

中文翻译：

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KLF2 通过 SCAP/SREBP 途径调节肝脏脂肪生成和血液胆固醇稳态的作用。

肝脏脂肪变性是一种常见的代谢性疾病，由脂质代谢失衡引起，涉及脂肪从头生成、脂肪酸摄取、脂肪酸氧化和极低密度脂蛋白（VLDL）分泌等多种过程。在这项研究中，我们发现转录因子KLF2在调节肝脏脂质代谢中发挥着至关重要的作用。在正常饮食喂养的 db/db 小鼠、C57BL/6J 小鼠和 CD36-/- 小鼠的肝脏中 KLF2 过度表达导致肝脏中脂质含量增加。此外，肝脏中过度表达 KLF2 的转基因小鼠 (ALB-Klf2) 在接受正常饮食后出现肝脏脂肪变性。我们发现 KLF2 通过增加 SCAP 的表达来促进脂肪生成，SCAP 是一种促进 SREBP 激活的分子伴侣，SREBP 是脂肪生成基因表达的主要转录因子。我们的机制研究表明，KLF2 通过与 SCAP 启动子结合并增加参与脂肪酸合成的基因表达来增强肝脏中的脂肪生成。KLF2表达的减少导致SCAP表达减少以及参与脂肪生成的SREBP1靶基因表达减少。KLF2 的过度表达还增加了 SREBP2 的激活及其下游靶标 SOAT1 的 mRNA 水平。在喂食高脂肪饮食的 C57BL/6J 小鼠中，KLF2 的过度表达增加了血液 VLDL 的分泌，而减少其表达则降低了血液胆固醇水平。我们的研究强调了肝脏 KLF2 通过 KLF2/SCAP/SREBPs 途径在调节脂质代谢中发挥关键作用的新颖性，这对于肝脏脂肪生成和维持血液胆固醇稳态至关重要。