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SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ

Nature Medicine volume 14, pages 656–666 (2008)Cite this article

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-δ (PPAR-δ) and co-repressors and thus inhibited Cpt1b, Ucp2 and Ucp3 expression. Upon agonist stimulation of PPAR-δ, KLF5 was deSUMOylated, and became associated with transcriptional activation complexes containing both the liganded PPAR-δ 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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Figure 1: Klf5+/− mice are protected from diet-induced obesity and metabolic dysfunction.
Figure 2: SUMO-modification of KLF5 is required for transrepression activity and recruitment of corepressors.
Figure 3: KLF5 interacts with PPAR-δ and binds the Cpt1b, Ucp3 and Ucp2 promoters with PPAR-δ and co-regulators.
Figure 4: Dynamic exchange of co-regulators and deSUMOylation induced by GW501516.
Figure 5: SUMOylation of KLF5 within transcriptional regulatory programs governing expression of genes related to fatty acid catabolism.
Figure 6: KLF5 has an essential role in the formation of transcriptional regulatory complexes that respond to GW501516 action on the target gene promoters.

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Acknowledgements

We gratefully acknowledge N. Yamanaka, M. Hayashi, Y. Tani and E. Magoshi for their excellent technical assistance. We thank M. Yamada (Gunma University) for providing pGL3-UCP2, C. Glass (University of California, San Diego) for providing FLAG-tagged cDNA encoding mouse NCoR, R. Evans (Salk Institute for Biological Studies) for providing cDNA encoding human SMRT and the Gal4-SMRT expression construct, R. Hay (University of Dundee) for providing pcDNA3-HA-SUMO1 and pcDNA3-HA-SUMO2, E. Yeh (University of Texas–Houston Health Science) for providing pcDNA3-SENP1, and P. Grimaldi (Universite de Nice-Sophia Antipolis) for providing pcDNA3-PPARδ. This study was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to R.N., I.M. and Y.O.), a research grant from the National Institute of Biomedical Innovation, Japan and Special Coordination Funds for Promoting Science and Technology from Japan Science and Technology Agency (to R.N.), and research grants from Japan Science and Technology Agency, NOVARTIS Foundation for the Promotion of Science, Kato Memorial Bioscience Foundation, Takeda Science Foundation, Cell Science Research Foundation and Tokyo Biochemical Research Foundation (to I.M.).

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  1. nagai-tky@umin.ac.jp

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan

    Yumiko Oishi, Ichiro Manabe, Katsuhito Fujiu, Koji Maemura & Ryozo Nagai

  2. Clinical Nutrition Program, National Institute of Health and Nutrition, 1-23-1, Toyama, Shinjuku, Tokyo, 162-8636, Japan

    Yumiko Oishi, Tetsuya Kubota, Naoto Kubota & Takashi Kadowaki

  3. Nano-Bioengineering Education Program, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan

    Ichiro Manabe

  4. Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo, 113-8655, Japan

    Kazuyuki Tobe, Mitsuru Ohsugi, Tetsuya Kubota, Naoto Kubota & Takashi Kadowaki

  5. First Department of Internal Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Kazuyuki Tobe

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Contributions

Y.O. developed the project, performed most of the experiments and data analysis and wrote the manuscript. I.M. developed and supervised the project, designed experiments, performed data analysis and wrote the manuscript. M.O., T. Kubota. and N.K. contributed to the mouse physiology studies. K.F. and K.M. contributed to the in vitro studies. K.T. and T. Kadowaki supervised the project and reviewed the manuscript. R.N. directed the project and reviewed the manuscript.

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Correspondence to Ichiro Manabe or Ryozo Nagai.

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Oishi, Y., Manabe, I., Tobe, K. et al. SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-δ. Nat Med 14, 656–666 (2008). https://doi.org/10.1038/nm1756

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