Abstract
Klf5 is a Transcriptional Regulator of Cardiac Med13 and Affects High Fat Diet-induced Obesity
Circulation, Vol.130(Supplement 2), A17916
American Heart Association's Scientific Sessions and Resuscitation Science Symposium, 2014 (Chicago, United States, 15-Nov-2014–19-Nov-2014)
2014
Abstract
Krüppel-like factors (KLF) are involved in cardiac and systemic metabolism. Our goal was to identify the metabolic role of cardiac KLF5, which showed the highest increase (8-fold) among all KLF isoforms as determined by whole genome microarray analysis of energy-starved hearts obtained from lipopolysaccharide (LPS)-treated mice. We therefore generated a cardiomyocyte-specific KLF5 knockout mouse (αMHC-KLF5-/-) and showed that the mice present 50% reduction of KLF5 in hearts and normal cardiac function. The αMHC-KLF5-/- mice were fed with high fat diet (HFD) for 6 weeks. HFD led to a more profound body weight increase of αMHC-KLF5-/- mice (35%) compared to HFD-fed C57BL/6 wild type mice (15%). This was associated with increased expression of PPARγ2 (2.6-fold), LpL (4.4-fold), CD36 (8.9-fold), DGAT2 (3.4-fold) and GLUT4 (3.5-fold) in white adipose tissue (WAT), as well as increased weight (35%) of WAT. Accordingly, HFD-fed αMHC-KLF5-/- mice had larger white adipocytes and brown adipocytes as shown by H&E staining and increased hepatic neutral lipid accumulation as shown by Oil-Red-O staining. Plasma glucose and triglyceride levels were not different between HFD-fed wt and αMHC-KLF5-/- mice. Metabolic cage analysis did not identify any significant changes in respiratory exchange ratio, caloric intake and activity. The obesogenic effect of cardiomyocyte-specific deletion of KLF5 resembles the phenotype of the αMHC-MED13-/- mice. We showed that αMHC-KLF5-/- mice had a 45% reduction in cardiac MED13 levels despite lack of changes in the expression levels of miR-208, a known regulator of MED13. Infection of a mouse cardiomyocyte cell line (HL-1) with a recombinant adenovirus expressing KLF5 (Ad-KLF5) increased MED13 expression (80%). Promoter analysis of mouse and human med13 genes identified two conserved potential KLF binding sites. Chromatin immunoprecipitation analysis of HL-1 cells treated with Ad-KLF5 showed enhanced binding of KLF5 on the -730/-714 bp region of the med13 gene promoter. In conclusion, KLF5 is a miR-208-independent, direct regulator of cardiac MED13 and affects systemic fatty acid metabolism and obesity.
Details
- Title
- Klf5 is a Transcriptional Regulator of Cardiac Med13 and Affects High Fat Diet-induced Obesity
- Authors
- Konstantinos Drosatos (Author)Nina M Pollak (Author)Michael J Jurczak (Author)Panagiotis Ntziachristos (Author)Chad M Trent (Author)Yunying Hu (Author)Iannis Aifantis (Author)Gerald I Shulman (Author)Ira J Goldberg (Author)
- Publication details
- Circulation, Vol.130(Supplement 2), A17916
- Conference details
- American Heart Association's Scientific Sessions and Resuscitation Science Symposium, 2014 (Chicago, United States, 15-Nov-2014–19-Nov-2014)
- Publisher
- Lippincott Williams & Wilkins
- Date published
- 2014
- ISSN
- 1524-4539; 0009-7322
- Organisation Unit
- University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99513767002621
- Output Type
- Abstract
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