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

Guo, Yanhong; Fan, Yanbo; Zhang, Jifeng; Lomberk, Gwen; Zhou, Zhou; Sun, Lijie; Mathison, Angela; Garcia-Barrio, Minerva T.; Zhang, Ji; Zeng, Lixia; Li, Lei; Pennathur, Subramaniam; Willer, Cristen J.; Rader, Daniel J.; Urrutia, Raúl; Chen, Y. Eugene

doi:10.1172/jci79048

Cited by 81 publications

(93 citation statements)

References 60 publications

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“…To determine the contribution of hepatic KLF14 to both ApoA-I and HDL-c production, they generated KLF14 knock-out mice which results in reduced plasma HDL-c concentration. Thus, the combined results of experiments using a wide variety of complementary genetic approaches firmly establish a regulatory role for KLF14 in HDL-c functionality and atherosclerosis [23]. In our study, T2DM patients have dyslipidemia, which could be related to down-regulation of KLF14 and, consequently decreased levels of HDL-c.…”

Section: Discussionsupporting

confidence: 62%

The Association between the KLF14 rs4731702 SNP and the Lipid Profile in Type 2 Diabetes Mellitus Patients: A Study in San Luis City, San Luis, Argentina

Alvarez¹,

Gomez²,

González³

et al. 2016

OALib

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The single nucleotide polymorphism (SNP) rs4731702 in the KLF14 transcription factor gene has been associated with type 2 diabetes mellitus (T2DM) and HDL-c concentrations. The aim of the present study was to determine the distribution of KLF14 rs4731702 SNP and evaluate the association between this SNP and serum lipid profile in T2DM patients in a patient population at San Luis province, Argentina. A total of 73 volunteers (26 T2DM patients and 47 healthy age-matched controls)were genotyped for KLF14 rs4731702 SNP by Tetra Primer ARMS-PCR. The KLF14 genotypes distribution among study groups was not significantly different. In T2DM patients, there was a difference in HDL-c values and TC/HDL-c ratio, with T carriers of the rs4731702 SNP (non C/C) having higher HLD-c and lower TC/HDL-c ratio values than C/C homozygotes (p = 0.0047 and 0.0041, respectively). HDL-c levels were higher in diabetic patients, without dyslipidemia, carrying the genotype non-C/C (p = 0.023). Conversely, TC and LDL-c levels were lower in diabetic patients, without dyslipidemia, in non-C/C carriers (p < 0.001). The results of the current study showed that T2DM is characterized by dyslipidemia, and that the alterations observed in the lipoprotein might be related to lower KLF14 activity in diabetic patients as a consequence of C/C genotype and insulin resistance.

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Section: Discussionsupporting

confidence: 62%

The Association between the KLF14 rs4731702 SNP and the Lipid Profile in Type 2 Diabetes Mellitus Patients: A Study in San Luis City, San Luis, Argentina

Alvarez¹,

Gomez²,

González³

et al. 2016

OALib

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“…Finally, in a recent study, perhexiline was found to activate Kruppel-like factor 14 and increase high density lipoprotein in animal models of atherosclerosis [61]. This finding raises the potential for an anti-atherogenic effect of perhexiline, which has not yet been evaluated formally.…”

Section: Perhexilinementioning

confidence: 97%

Drugs that Affect Cardiac Metabolism: Focus on Perhexiline

Chong

Sallustio

Horowitz

2016

Cardiovasc Drugs Ther

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Approaches to the pharmacotherapy of angina pectoris have previously centred on the concept that a transient imbalance between myocardial oxygen "demand" and supply within the myocardium can best be addressed by reducing demand (for example, with β-adrenoceptor antagonist) or by increasing availability of blood (via coronary vasomotor reactivity adjustment or coronary revascularization). However, this principle is potentially challenged by the emergence of cases of angina unsuitable for such therapies (for example because of concomitant severe systolic heart failure) and by the recognition that impaired myocardial energetics may precipitate angina in the absence of fixed or variable coronary obstruction (for example in hypertrophic cardiomyopathy). The past 20 years have seen the re-emergence of a class of anti-anginal agents which act primarily by improving efficiency of myocardial oxygen utilization, and thus can correct impaired energetics, simultaneously treating angina and heart failure symptoms. We review the principles underlying the safe use of such agents, beginning with the prototype drug perhexiline maleate, which despite complex pharmacokinetics and potential hepato- or neuro-toxicity has emerged as an attractive management option in many "complicated" cases of angina pectoris.

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“…KLF14 regulates generation of signaling lipids in the liver by transactivating expression of sphingosine kinase 1 (SK1) 209 . KLF14 also regulates expression of apolipoprotein A1 and increases high-density lipoprotein-C 210 .…”

Section: Roles In the Digestive System And Diseasesmentioning

confidence: 99%

SP and KLF Transcription Factors in Digestive Physiology and Diseases

Kim

Bialkowska

et al. 2017

Gastroenterology

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Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies demonstrate that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.

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

Cited by 81 publications

References 60 publications

The Association between the KLF14 rs4731702 SNP and the Lipid Profile in Type 2 Diabetes Mellitus Patients: A Study in San Luis City, San Luis, Argentina

The Association between the KLF14 rs4731702 SNP and the Lipid Profile in Type 2 Diabetes Mellitus Patients: A Study in San Luis City, San Luis, Argentina

Drugs that Affect Cardiac Metabolism: Focus on Perhexiline

SP and KLF Transcription Factors in Digestive Physiology and Diseases

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