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 4

Drug screening identifies perhexiline as an activator of KLF14.

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Drug screening identifies perhexiline as an activator of KLF14. (A) Diag...
(A) Diagram of the chemical structure of the perhexiline maleate salt. (B and C) Luciferase activity of reporters was analyzed in HepG2 cells transfected with pGL4-KLF-luc or pGL4–ApoA-I–Luc constructs after 12 hours treatment with 10 μM perhexiline or DMSO. **P < 0.01, Student’s t test. Values represent mean ± SEM; n = 3. (D) HepG2 cells were infected with AdshLacZ or AdshKLF14 for 48 hours and then incubated with 10 μM perhexiline for 24 hours in DMEM containing 0.2% BSA. The ApoA-I concentrations in the medium were detected by ELISA. *P < 0.05, 2-way ANOVA and multiple comparisons. Values represent mean ± SEM; n = 6. (E) HepG2 cells were treated with DMSO or perhexiline at 10 μM for indicated time points in DMEM containing 0.2% BSA, and ApoA-I production was detected by Western blot. (F) HepG2 cells were treated with DMSO or perhexiline at indicated dosage for 24 hours in DMEM containing 0.2% BSA, and ApoA-I production was detected by Western blot. (G) HepG2 cells were treated with DMSO, perhexiline, RVX-208, or etomoxir at 10 μM for 24 hours in DMEM containing 0.2% BSA, and ApoA-I production was detected by Western blot. Quantifications from 3 independent experiments are shown in E–G, and values represent mean ± SEM. *P < 0.05; **P < 0.01, 2-way ANOVA and multiple comparisons.