Abstract 17916: Klf5 is a Transcriptional Regulator of Cardiac Med13 and Affects High Fat Diet-induced Obesity
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.
Author Disclosures: K. Drosatos: None. N.M. Pollak: None. M. Jurczak: None. P. Ntziachristos: None. C.M. Trent: None. Y. Hu: None. I. Aifantis: None. G.I. Shulman: None. I.J. Goldberg: None.
- © 2014 by American Heart Association, Inc.