SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ
SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ
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DOI：
10.1038/nm1756
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发表时间：
2008-06-01
期刊：
影响因子：
82.9
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Oishi, Yumiko;Manabe, Ichiro;Nagai, Ryozo
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。在这里，我们表明，Kruppel样转录因子5（KLF 5）是一个重要的调节能量代谢。Klf 5（+/-）小鼠对高脂肪诱导的肥胖、高胆固醇血症和葡萄糖耐受不良有抵抗力，尽管比野生型小鼠消耗更多的食物。这可能部分反映了他们的能量消耗增加。Klf 5（+/-）小鼠比目鱼肌中参与脂质氧化和能量解偶联的基因（包括编码肉毒碱棕榈酰转移酶-1b（Cpt 1b）和解偶联蛋白2和3（Ucp 2和Ucp 3）的基因）的表达上调。在基础条件下，KLF 5修饰的小泛素相关的修饰剂（SUMO）蛋白与转录抑制调控复合物含有unliganded过氧化物酶体增殖物激活受体-δ（PPAR-delta）和共阻遏物，从而抑制Cpt 1b，Ucp 2和Ucp 3的表达。在激动剂刺激PPAR-delta后，KLF 5被去SUMO化，并与含有配体PPAR-delta和CREB结合蛋白（CBP）的转录激活复合物结合。这种激活复合物增加了Cpt 1b，Ucp 2和Ucp 3的表达。因此，SUMO化似乎是影响KLF 5功能和控制脂质代谢的转录调控程序的分子开关。
Obesity and metabolic syndrome are increasingly recognized as major risk factors for cardiovascular disease. Herein we show that Kruppel-like transcription factor 5 (KLF5) is a crucial regulator of energy metabolism. Klf5(+/-) mice were resistant to high fat-induced obesity, hypercholesterolemia and glucose intolerance, despite consuming more food than wild-type mice. This may in part reflect their enhanced energy expenditure. Expression of the genes involved in lipid oxidation and energy uncoupling, including those encoding carnitine-palmitoyl transferase-1b (Cpt1b) and uncoupling proteins 2 and 3 (Ucp2 and Ucp3), was upregulated in the soleus muscles of Klf5(+/-) m ice. Under basal conditions, KLF5 modified with small ubiquitin-related modifier (SUMO) proteins was associated with transcriptionally repressive regulatory complexes containing unliganded peroxisome proliferator-activated receptor-delta (PPAR-delta) and co-repressors and thus inhibited Cpt1b, Ucp2 and Ucp3 expression. Upon agonist stimulation of PPAR-delta, KLF5 was deSUMOylated, and became associated with transcriptional activation complexes containing both the liganded PPAR-delta and CREB binding protein (CBP). This activation complex increased the expression of Cpt1b, Ucp2 and Ucp3. Thus, SUMOylation seems to be a molecular switch affecting function of KLF5 and the transcriptional regulatory programs governing lipid metabolism.