Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Abstract

Rationale Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown. Objective To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara. Methods and Results We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels. Conclusions Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.

Lack of Adipocyte Purinergic P2Y6Receptor Greatly Improves Whole Body Glucose Homeostasis

“…Strikingly, acute P2Y 6 In addition to JNK activation, we observed that P2Y 6 R stimulation resulted in downstream binding of cJUN to the PPARα promoter, thereby reducing PPARα transcription in white adipocytes. Such regulation of PPARα transcription by cJUN has also been reported in cardiomyocytes (53). We also demonstrated that JNK activation downstream of the P2Y 6 R regulates PPARα transcription, as treatment of cells with JNK inhibitor did not change Ppara mRNA levels.…”

Hydrogen Sulfide Regulates Krüppel‐Like Factor 5 Transcription Activity via Specificity Protein 1 S‐Sulfhydration at Cys664 to Prevent Myocardial Hypertrophy

“…KLF5 can also be regulated by a variety of transcription factors and nuclear receptors, such as retinoic acid receptor α, nuclear factor κB, PPAR‐γ, and p300 . In our study, we found that H 2 S can decrease SP‐1 binding to the KLF5 promoter and thus suppress KLF5 expression.…”

“…KLF5 can also be regulated by a variety of transcription factors and nuclear receptors, such as retinoic acid receptor a, nuclear factor jB, PPAR-c, and p300. 26,27 In our study, we found that H 2 S can decrease SP-1 binding to the KLF5 promoter and thus suppress KLF5 expression. There are abundant exposed cysteine groups in the structure of SP-1, and it is possible that H 2 S may target SP-1 by S-sulfhydration.…”

eIF5a reduction via decreased Klf5 leads to cell senescence by mitochondrial fission in VSMCs

“…These results indicate that dysregulation of mitochondrial dynamics can drive VSMC senescence and excessive ROS production. Although cardiomyocyte Klf5 was recently identified as a regulator of cardiac metabolism by directly activating transcription of PPARα and regulating lipid metabolism (Drosatos et al, 2016), whether and how Klf5 regulates mitochondrial dynamics is currently unclear.…”