SUMOylation of Krueppel-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 Krueppel-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.
Mesh Terms:
Animals, Body Temperature, COS Cells, Cell Line, Cercopithecus aethiops, Cholesterol, Crosses, Genetic, Genes, Reporter, Glucose Tolerance Test, Heterozygote, Kruppel-Like Transcription Factors, Leptin, Lipid Metabolism, Luciferases, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myoblasts, Oxygen Consumption, PPAR delta, Small Ubiquitin-Related Modifier Proteins, Transcription, Genetic
Animals, Body Temperature, COS Cells, Cell Line, Cercopithecus aethiops, Cholesterol, Crosses, Genetic, Genes, Reporter, Glucose Tolerance Test, Heterozygote, Kruppel-Like Transcription Factors, Leptin, Lipid Metabolism, Luciferases, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myoblasts, Oxygen Consumption, PPAR delta, Small Ubiquitin-Related Modifier Proteins, Transcription, Genetic
Nat. Med.
Date: Jun. 01, 2008
PubMed ID: 18500350
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