SUMOylation of Krüppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta.
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-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.
Oishi
Yumiko
Y
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan.
Manabe
Ichiro
I
Tobe
Kazuyuki
K
Ohsugi
Mitsuru
M
Kubota
Tetsuya
T
Fujiu
Katsuhito
K
Maemura
Koji
K
Kubota
Naoto
N
Kadowaki
Takashi
T
Nagai
Ryozo
R
D000818:Animals; D001831:Body Temperature; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000097:blood; D003433:Crosses, Genetic; D017930:Genes, Reporter; D005951:Glucose Tolerance Test; D006579:Heterozygote; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010101:Oxygen Consumption; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D020738:Leptin; D047494:PPAR delta; D025841:Small Ubiquitin-Related Modifier Proteins; D002784:Cholesterol; D008156:Luciferases