TY - JOUR
T1 - Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production
AU - Guo, Yanhong
AU - Fan, Yanbo
AU - Zhang, Jifeng
AU - Lomberk, Gwen A.
AU - Zhou, Zhou
AU - Sun, Lijie
AU - Mathison, Angela J.
AU - Garcia-Barrio, Minerva T.
AU - Zhang, J.
AU - Zeng, Lixia
AU - Li, Lei
AU - Pennathur, Subramaniam
AU - Willer, Cristen J.
AU - Rader, Daniel J.
AU - Urrutia, Raul
AU - Chen, Y. Eugene
PY - 2015/10/1
Y1 - 2015/10/1
N2 - Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Kruppel-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.Gmail: Acknowledgments This work was supported in whole or in part by NIH grants HL068878, HL105114, and HL088391 (to Y.E. Chen), DK89503 and DK097153 (to S. Pennathur), DK52913 (to R. Urrutia), and CA178627 (to G.A. Lomberk) and by American Heart Association National Scientist Development grants 15SDG24470155 (to Y. Guo) and 14SDG19880014 (to Y. Fan).
AB - Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Kruppel-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.Gmail: Acknowledgments This work was supported in whole or in part by NIH grants HL068878, HL105114, and HL088391 (to Y.E. Chen), DK89503 and DK097153 (to S. Pennathur), DK52913 (to R. Urrutia), and CA178627 (to G.A. Lomberk) and by American Heart Association National Scientist Development grants 15SDG24470155 (to Y. Guo) and 14SDG19880014 (to Y. Fan).
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U2 - 10.1172/JCI79048
DO - 10.1172/JCI79048
M3 - Article
C2 - 26368306
AN - SCOPUS:84943222952
SN - 0021-9738
VL - 125
SP - 3819
EP - 3830
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -