Journal Club Summary

SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta.

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The selected article is over the involvement of the gene Klf5 in fatty oxidation in skeletal muscle. The data presented in this article suggests that KLF5 is a transcriptional repressor of fatty acid oxidation genes in skeletal muscle. The proposed mechanism is that KLF5 (in complex with C/EBP and PPAR-delta ) is SUMOylated (via SUMO1) allowing for the recruitment of co-repressors (NCoR and SMRT) thereby inhibiting PPAR-delta and preventing the transcription of target genes involved in fatty acid oxidation, such as Cpt1b, Ucp2 and Ucp3. Once PPAR-delta is agonized there is deSUMOylation of KLF5 and recruitment of CBP, allowing for transcription of PPAR-delta targets and initiation of transcription of fatty acid oxidation associated genes.

Our group thought this data was fairly convincing overall; however one key experiment was lacking. They are suggesting that PPAR-delta is required for the transcription of these fatty acid oxidation genes and that SUMOylated KLF5 blocks this, but they did not test the effects of knocking out PPAR-delta, which we believe would be the best study to support their claims. Additionally, the background information provided to explain what lead them to look at KLF5 and its SUMOylation-associated repressive actions was incomplete and somewhat unclear.

Other articles discussed this week included:

  • Xu Z, Xu X, Zhong M, Hotchkiss IP, Lewandowski RP, et al. (2011) Ambient particulate air pollution induces oxidative stress and alterations of mitochondria and gene expression in brown and white adipose tissues. Part Fibre Toxicol 8: 20. doi:10.1186/1743-8977-8-20.
  • Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP, et al. (2014) 11beta-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci U S A 111: E2482–E2491. doi:10.1073/pnas.1323681111.
  • Hamadeh MJ, Devries MC, Tarnopolsky M a. (2005) Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise. J Clin Endocrinol Metab 90: 3592–3599. doi:10.1210/jc.2004-1743.
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