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Article
Nature Medicine 14, 656 - 666 (2008)
Published online: 25 May 2008 | doi:10.1038/nm1756
SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-
Yumiko Oishi1,2, Ichiro Manabe1,3, Kazuyuki Tobe4,5, Mitsuru Ohsugi4, Tetsuya Kubota2,4, Katsuhito Fujiu1, Koji Maemura1, Naoto Kubota2,4, Takashi Kadowaki2,4 & Ryozo Nagai1
Abstract
Obesity and metabolic syndrome are increasingly recognized as major risk factors for cardiovascular disease. Herein we show that Krüppel-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+/- mice. 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-
(PPAR-) and co-repressors and thus inhibited Cpt1b, Ucp2 and Ucp3 expression. Upon agonist stimulation of PPAR-, KLF5 was deSUMOylated, and became associated with transcriptional activation complexes containing both the liganded PPAR- 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.
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