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 1

Overexpression of KLF14 increases both HDL-C and ApoA-I levels and cholesterol efflux capacity.

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Overexpression of KLF14 increases both HDL-C and ApoA-I levels and chole...
Adenoviral vectors containing LacZ (AdLacZ) or human KLF14 (AdKLF14) (5 × 108 pfu per mouse) were administered via tail vein injection to C57BL/6 mice fed HFD for 12 weeks (n = 10 per group). Serum samples were collected at day 6 and subjected individually to analytical chemistry to measure HDL-C (A), TC (B), LDL-C (C), TG (D), and fasting blood glucose (E) or to determine cholesterol and TG levels from pooled samples by FPLC (fractions 1 to 40) (F and G). *P < 0.05, Student’s t test. (H) The ABCA1-mediated cholesterol efflux capacity of serum from AdKLF14- or AdLacZ-treated mice is expressed as the percentage of cholesterol efflux of total cell cholesterol (n = 10 per group). *P < 0.05, Student’s t test. Representative Western blot results show that AdKLF14-treated mice exhibited increased expression of ApoA-I levels in the liver (I) and serum (J). (K) Quantifications of ApoA-I levels in the serum from AdLacZ and AdKLF14-treated mice by Western blot (n = 10 per group). Values represent mean ± SEM. **P < 0.01, Student’s t test.