Transcription factor networks in blood vessel-metabolic system crosstalk and metabolic syndrome

肥胖和代谢综合征越来越被认为是心血管疾病的主要危险因素。在这个项目中，我们分析了Kruppel样转录因子5（KLF 5）在代谢综合征和心血管疾病中的作用。KLF 5杂合敲除（KLF 5 ^<+/->）小鼠对高脂肪诱导的肥胖、高胆固醇血症、葡萄糖耐受不良和肝脂肪变性具有抗性，尽管消耗的食物比野生型小鼠多。这可能部分反映了它们增加的系统O_2消耗，表明能量消耗增加。在KLF 5 ^<+/->小鼠的比目鱼肌和KLF 5被敲低的C2Cl 2肌管中，参与脂质氧化和能量解偶联的基因表达上调。我们证明了KLF 5是能量代谢的重要调节因子。KLF 5与过氧化物酶体增殖物激活受体δ共同作用，在调控脂肪酸催化剂相关基因表达的转录调控程序中发挥核心作用。KLF 5在平滑肌细胞中与RAR相互作用，不同组织中相互作用伴侣的差异似乎决定了KLF 5的组织特异性功能。

Obesity and metabolic syndrome are increasingly recognized as major risk factors for cardiovascular disease. In this project we analyzed the roles played by Kruppel-like transcription factor 5 (KLF5) in metabolic syndrome and cardiovascular disease. KLF5 heterozygous knockout (KLF5^<+/->) mice were resistant to high-fat-induced obesity, hypercholesterolemia, glucose intolerance and hepatic steatosis, despite consuming more food than wild-type mice. This may in part reflect their increased systemic O_2 consumption, indicating enhanced energy expenditure. Expression of the genes involved in lipid oxidation and energy uncoupling was upregulated in the soleus muscles of KLF5^<+/-> mice and in C2Cl2 myotubes in which KLF5 was knocked down. We demonstrated that KLF5 is a crucial regulator of energy metabolism. KLF5 acts with PPARδ to play a central role in transcriptional regulatory programs governing expression of genes related to fatty acid catabolism. KLF5 interacts with RAR in smooth muscle cells and the differences in interacting partners in different tissues appear to determine tissue-specific functions of KLF5.