Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production
Yanhong Guo, … , Raul Urrutia, Y. Eugene Chen
Yanhong Guo, … , Raul Urrutia, Y. Eugene Chen
Published September 14, 2015
Citation Information: J Clin Invest. 2015;125(10):3819-3830. https://doi.org/10.1172/JCI79048.
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Research Article Cardiology

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Abstract

Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E–deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis.

Authors

Yanhong Guo, Yanbo Fan, Jifeng Zhang, Gwen A. Lomberk, Zhou Zhou, Lijie Sun, Angela J. Mathison, Minerva T. Garcia-Barrio, Ji Zhang, Lixia Zeng, Lei Li, Subramaniam Pennathur, Cristen J. Willer, Daniel J. Rader, Raul Urrutia, Y. Eugene Chen

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Figure 2

KLF14 is a regulator of APOA1 expression.

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KLF14 is a regulator of APOA1 expression. HepG2 cells were infected with...
HepG2 cells were infected with AdLacZ or AdKLF14 for 24 hours and then incubated in medium containing ActD (5 μg/ml) or DMSO for another 24 hours (n = 3). KLF14 (A) and APOA1 (B) mRNA levels were determined by real-time qPCR. **P < 0.01, 2-way ANOVA and multiple comparisons. (C) The structure of human APOA1 promoter used in the luciferase assays indicating 2 putative CACCC-box KLF-binding sites. Expression of KLF14 with human APOA1 promoter assay demonstrated that KLF14 significantly increased ApoA-I luciferase activity (n = 3). **P < 0.01, compared with control vector, 2-way ANOVA and multiple comparisons. (D) Mutations of the 2 putative KLF-binding sites demonstrated ApoA-I expression is dependent on KLF14 and CACCC-box binding sites (n = 3). **P < 0.01, compared with pGL4-basic vector; ##P < 0.01, compared with APOA1 promoter WT, 2-way ANOVA and multiple comparisons. (E) ChIP assay revealed significant enrichment of KLF14 protein on the human APOA1 promoter in HepG2 cells (n = 3). *P < 0.05, 2-way ANOVA and multiple comparisons. (F) Luciferase activity assay demonstrated that KLF14, not KLF2, KLF4, or KLF11, led to an increase in APOA1 promoter activity in HepG2 cells (n = 3). **P < 0.01, 2-way ANOVA and multiple comparisons. Representative of at least 3 experiments.