Discovery of gemfibrozil analogues that activate PPARα and enhance the expression of gene CPT1A involved in fatty acids catabolism

Filippis, Barbara De; Giancristofaro, Antonella; Ammazzalorso, Alessandra; D’Angelo, Alessandra; Fantacuzzi, Marialuigia; Giampietro, Letizia; Maccallini, Cristina; Petruzzelli, Michele; Amoroso, Rosa

doi:10.1016/j.ejmech.2011.08.022

Cited by 28 publications

(19 citation statements)

References 24 publications

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“…Activation of PPAR ␣ via therapeutic agents such as fi brates, which lower CVD risk, increases CPT1A expression as do long-chain fatty acids ( 27,28 ). Our results suggest that increases in methylation Supplemental Material can be found at:…”

Section: Discussionmentioning

confidence: 77%

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

Frazier‐Wood

Aslibekyan

Absher

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCholesterol concentrations from lipoprotein fractions are some of the most commonly used clinical biomarkers of cardiovascular and metabolic disease risk ( 1 ). However, LDL cholesterol and HDL cholesterol concentrations do not account for all lipid-based CVD risk ( 1 ). In addition, the causal role of HDL cholesterol with CVD is debated ( 2 ). Thus, alternative lipid biomarkers of CVD are useful for gaining a more complete CVD risk profi le and for exploring the mechanisms that may underlie cardiovascular events.Within each lipoprotein fraction, the constituent particles are heterogeneous in their size and composition. The particles forming the VLDL, LDL, and HDL fractions may be further subdivided into subfractions based on their size, which partially refl ects the cholesterol content of the particle. Specifi c constellations of subfractions have been associated with insulin resistance (IR) and atherosclerosis ( 3-9 ).Currently, lipoprotein subfractions are limited in their clinical utility due to a lack of evidence that they con vey information on the likelihood of experiencing an adverse cardiovascular event over and above that of traditional anthropometric, lipid, and demographic risk factors. However, identifying the genetic factors associated with lipoprotein subfractions may provide a more thorough understanding of the pathways that regulate lipoprotein composition and metabolism and so shed light on the etiology of atherosclerosis and IR. Numerous genetic loci have been associated with lipoprotein subfractions at Abstract Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the fi rst systematic screen of the genome to determine associations between methylation status at ‫ف‬ 470,000 cytosine-guanine dinucleotide (CpG) sites in CD4 + T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identifi ed two CpGs, both in the carnitine palmitoyltransferase-1A ( CPT1A ) gene, which reached signifi cant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases ( P < 1.1 × 10 ؊ 7 in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10 ؊ 12 in the full sample). CPT1A is regulated by PPAR ␣ , a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this g...

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Section: Discussionmentioning

confidence: 77%

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

Frazier‐Wood

Aslibekyan

Absher

et al. 2014

Journal of Lipid Research

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“…Because long-chain fatty acids can be converted into triglycerides via the transshipment of the carnitine palmitoyl transferase (CPT) enzyme system, 28 thus, the stimulation of CPT1 expression following either YCS or YCR supplementation was related to the decrease of TC and LDL-C. It was more important to know that CPT1 is a target gene of PPAR 29 and the mechanism of PPAR for transporting fatty acids into hepatocyte mitochondria could be associated with the increasing effect of PPAR on CPT1 in the liver, 30 which also reveals the consistency of expression of PPAR and CPT1 . Moreover, HMG-CoA is a regulator of cholesterol biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of hyperglycemia in diabetic mice by autolysates from β‐mannanase‐treated brewer's yeast

et al. 2019

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BACKGROUND Diabetes mellitus is a serious chronic disease, characterized by hyperglycemia. This study administered either β‐mannanase‐treated yeast cell autolysis supernatant (YCS) or yeast cell‐wall residues after autolysis (YCR) to investigate their influence on the alleviation of diabetes in a diabetic mouse model. RESULTS Application of either YCS or YCR led to body weight gain, blood glucose reduction, and an improvement in lipid composition in the diabetic mice. Administration of YCS was more effective in inhibiting oxidative stress than YCR. The expression of PPARα and CPT1α was enhanced, improving lipid biosynthesis, and Trx1 and HIF‐1‐α genes were downregulated due to the activation of thioredoxin following the interventions, indicating that the processes of lipid metabolism and oxidative stress were heavily involved in the reduction of diabetic characteristics following the interventions. The current study revealed that consumption of YCR also led to a reduction in hyperglycemia, this being associated with its richness in mineral elements, such as chromium and selenium. CONCLUSION This study may highlight the potential of both YCS and YCR as functional ingredients in dietary formula for improving diabetic syndromes. © 2019 Society of Chemical Industry

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“…Different isoforms of PPAR have been linked to upregulation of certain FAO enzymes or overall FAO activities in various cellular contexts 41,49,51,52 . Therefore, pharmacological antagonists of PPARs represent another class of FAO inhibitors that downregulate FAO via transcriptional repression of FAO pathway enzymes 41,52,53 . By assessing effects of antagonists of respective PPAR isoforms, we found that FAO in MCF-7 and T47D cells was most sensitive to the PPARα antagonist GW6471.…”

Section: Discussionmentioning

confidence: 99%

“…The peroxisome proliferator-activated receptors (PPARs) of the ligand-activated nuclear receptor superfamily are the most prominent transcriptional regulators of FAO enzymes 49,50 . They act essentially as environmental fat sensors and activators of FAO 41,51,52 . Antagonists of PPARα, PPARβ/δ and PPARγ have been reported to inhibit FAO in different experimental settings 41,52,53 .…”

Section: Assessment Of Putative Fao Inhibitorsmentioning

confidence: 99%

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Functional analysis of molecular and pharmacological modulators of mitochondrial fatty acid oxidation

Wang

Devarakonda

et al. 2020

Sci Rep

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fatty acid oxidation (fAo) is a key bioenergetic pathway often dysregulated in diseases. the current knowledge on fAo regulators in mammalian cells is limited and sometimes controversial. previous FAO analyses involve nonphysiological culture conditions or lack adequate quantification. We herein described a convenient and quantitative assay to monitor dynamic fAo activities of mammalian cells in physiologically relevant settings. the method enabled us to assess various molecular and pharmacological modulators of the fAo pathway in established cell lines, primary cells and mice. Surprisingly, many previously proposed fAo inhibitors such as ranolazine and trimetazidine lacked FAO-interfering activity. In comparison, etomoxir at low micromolar concentrations was sufficient to saturate its target proteins and to block cellular fAo function. oxfenicine, on the other hand, acted as a partial inhibitor of fAo. As another class of fAo inhibitors that transcriptionally repress fAo genes, antagonists of peroxisome proliferator-activated receptors (ppARs), particularly that of ppARα, significantly decreased cellular FAO activity. Our assay also had sufficient sensitivity to monitor upregulation of fAo in response to environmental glucose depletion and other energy-demanding cues. Altogether this study provided a reliable fAo assay and a clear picture of biological properties of potential fAo modulators in the mammalian system.

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Discovery of gemfibrozil analogues that activate PPARα and enhance the expression of gene CPT1A involved in fatty acids catabolism

Cited by 28 publications

References 24 publications

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

Regulation of hyperglycemia in diabetic mice by autolysates from β‐mannanase‐treated brewer's yeast

Functional analysis of molecular and pharmacological modulators of mitochondrial fatty acid oxidation

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