title: 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.forename: Yanhong
authors.initials: Y
authors.lastname: Guo
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Fan
authors.forename: Jifeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.forename: Lijie
authors.initials: L
authors.lastname: Sun
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Mathison
authors.forename: Minerva T
authors.initials: MT
authors.lastname: Garcia-Barrio
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.forename: Lixia
authors.initials: L
authors.lastname: Zeng
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control* / Q000628:therapy; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood*; D004036:Diet, Atherogenic; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000819:agonists / Q000502:physiology*; D020738:Leptin / Q000172:deficiency; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010480:Perhexiline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051703:Sp Transcription Factors / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; C417549:KLF14 protein, human; C558181:Klf14 protein, mouse; D051741:Kruppel-Like Transcription Factors; D020738:Leptin; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D051703:Sp Transcription Factors; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D010480:Perhexiline