Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production. J Clin Invest 2015 Oct 01;125(10):3819-30
Date
09/15/2015Pubmed ID
26368306Pubmed Central ID
PMC4607137DOI
10.1172/JCI79048Scopus ID
2-s2.0-84943222952 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
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.
Author List
Guo Y, Fan Y, Zhang J, Lomberk GA, Zhou Z, Sun L, Mathison AJ, Garcia-Barrio MT, Zhang J, Zeng L, Li L, Pennathur S, Willer CJ, Rader DJ, Urrutia R, Chen YEAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinAngela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApolipoprotein A-I
Apolipoproteins E
Atherosclerosis
Cholesterol
Cholesterol, HDL
Diet, Atherogenic
Drug Evaluation, Preclinical
Gene Expression Regulation
Genetic Therapy
Genetic Vectors
Genome-Wide Association Study
Hep G2 Cells
Humans
Hyperlipoproteinemia Type II
Kruppel-Like Transcription Factors
Leptin
Liver
Mice
Mice, Inbred C57BL
Mice, Obese
Perhexiline
RNA, Messenger
Recombinant Fusion Proteins
Sp Transcription Factors
Sterol Regulatory Element Binding Proteins