Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production
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
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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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 5

Administration of perhexiline increased HDL-C levels in vivo.

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Administration of perhexiline increased HDL-C levels in vivo. C57BL/6J m...
C57BL/6J mice placed on a HFD for 12 weeks were treated with DMSO or perhexiline maleate salt (10 mg/kg/d) for 5 consecutive days by gavage administration, and plasma samples were collected at day 7 (n = 10 per group). HDL-C (A), TC (B), LDL-C (C), and TG (D) levels were measured. *P < 0.05, Student’s t test. (E) The ABCA1-mediated cholesterol efflux capacity of serum from DMSO- or perhexiline-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. Pooled serum samples from DMSO- or perhexiline-treated mice were assayed by HPLC, and cholesterol (F) and TG (G) levels (fractions 1 to 32) were determined. (H–K) KLF14-LKO and littermate control mice were treated with DMSO or perhexiline maleate salt (10 mg/Kg/d) for 5 consecutive days by gavage administration, and plasma samples were collected at day 7 (n = 5–8 for each genotype). HDL-C levels were determined (H) and ApoA-I levels were quantified by Western blot analysis (I) (n = 5–8 for each genotype). (J and K) qRT-PCR analysis showing the expression levels of Klf14 and Apoa1 in indicated groups. Data are expressed relative to 18S RNA (n = 5–8 for each genotype). Values represent mean ± SEM. *P < 0.05; **P < 0.01, 2-way ANOVA and multiple comparisons.