Metabolomic and Genetic Analysis of Biomarkers for Peroxisome Proliferator-Activated Receptor α Expression and Activation

Zhen, Yueying; Krausz, Kristopher W.; Chen, Chi; Idle, Jeffrey R.; Gonzalez, Frank J.

doi:10.1210/me.2007-0150

Cited by 70 publications

(78 citation statements)

References 28 publications

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“…Variations of this compound have been observed in previous metabolomics studies (Li et al 2013;Zhen et al 2007). …”

Section: Biological Interpretationsupporting

confidence: 62%

“…This compound was significantly elevated in the urine of mice treated with a peroxisome proliferator-activated receptor (PPARα) agonist, suggesting that this metabolite could be a potential urinary biomarker of PPARα agonists (Zhen et al 2007). In this context, the activation of PPARα through diet or by synthetic agonists may cause an improvement in lipid profile and by extension impact on cardiovascular health.…”

Section: Biological Interpretationmentioning

confidence: 99%

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Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

et al. 2014

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Bread is one of the most widely consumed foods. Its impact on human health is currently of special interest for researchers. We aimed to identify biomarkers of bread consumption by applying a nutrimetabolomic approach to a free-living population. An untargeted HPLC-q-TOF-MS and multivariate analysis was applied to human urine from 155 subjects stratified by habitual bread consumption in three groups: non-consumers of bread (NCB, n=56), white-bread consumers (WHB, n=48) and whole-grain bread consumers (WGB, n=51). The most differential metabolites (VIP ≥1.5) included compounds originating from cereal plant phytochemicals such as benzoxazinoids and alkylresorcinol metabolites, and compounds produced by gut microbiota (such as enterolactones, hydroxybenzoic and dihydroferulic acid metabolites). Pyrraline, riboflavin, 3-indolecarboxylic acid glucuronide, 2,8-dihydroxyquinoline glucuronide and N-α-acetylcitrulline were also tentatively identified. In order to combine multiple metabolites 2 in a model to predict bread consumption, a stepwise logistic regression analysis was used.Receiver operating curves were constructed to evaluate the global performance of individual metabolites and their combination. The area under the curve values [AUC (95% CI)] of combined models ranged from 77.8% (69.1%-86.4%) to 93.7% (89.4%-98.1%), whereas the AUC for the metabolites included in the models had weak values when they were evaluated individually: from 58.1 % (46.6-69.7 %) to 78.4% (69.8%-87.1%). Our study showed that a daily bread intake significantly impacted on the urinary metabolome, despite being examined under uncontrolled free-living conditions. We further concluded that a combination of several biomarkers of exposure is better than a single biomarker for the predictive ability of discriminative analysis.

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“…Variations of this compound have been observed in previous metabolomics studies (Li et al 2013;Zhen et al 2007). …”

Section: Biological Interpretationsupporting

confidence: 62%

Section: Biological Interpretationmentioning

confidence: 99%

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

et al. 2014

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“…A recent metabolomic study observed several nicotinamide metabolites to be elevated in the urine of both T2DM rodents and T2DM humans. Interestingly, these metabolites were also reported to be biomarkers for peroxisome proliferator-activated receptor ␣ activation (10,65,66). Given the clear role of peroxisome proliferator-activated receptor ␣ and its family members in fatty acid metabolism, pipecolic acid and nicotinamide metabolites as diagnostic biomarkers for T2DM in human patients should be evaluated.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus

Patterson

Bonzo

et al. 2011

Journal of Biological Chemistry

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To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n ‫؍‬ 10) and T2DM (n ‫؍‬ 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na ؉ -dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.Type 2 diabetes mellitus (T2DM), 4 the most common type of diabetes, is a significant, costly, and rapidly expanding public health concern worldwide. T2DM is associated with microvascular (nephropathy, retinopathy, and neuropathy) and macrovascular (coronary artery disease and peripheral vascular disease) pathologies resulting in a complex, multifactorial metabolic phenotype. Therefore, understanding the molecular pathogenesis and progression of T2DM, its associated and varied complications, and its effects on numerous organ systems is not trivial. The emerging field of small molecule profiling, or metabolomics, has already provided new perspectives on T2DM (1-5). As the end products of all cellular processes, global metabolite profiling may represent the best and largest net with which to capture changes originating from epigenomic, genomic, transcriptomic, and proteomic alterations.Metabolomics aims to identify and quantify all small molecules as they may be the most accurate indicators of cellular physiology (6). Moreover, metabolomics is an NIH Roadmap Initiative and was listed as a research priority in the American Society of Nephrology Renal Research Report (7). Metabolomic studies of T2DM have utilized a variety of animal models (e.g. db/db mice, streptozotocin-treated mice, Zucker...

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“…Recent studies have demonstrated the power of mass spectrometry-based metabolomics to profi le metabolic pathways to reveal the mechanism of action of nuclear receptors and the metabolic fate of drugs (9)(10)(11)(12). Metabolomics has revealed the downregulated tryptophan-nicotinamide pathways following Wy-14,643 treatment ( 9 ) and the decreased excretion of carnitine-conjugated metabolites by fenofi brate treatment in humans ( 13 ).…”

Section: Identifi Cation and Quantitation Of Urinary And Serum Metabomentioning

confidence: 99%

“…Metabolomics has revealed the downregulated tryptophan-nicotinamide pathways following Wy-14,643 treatment ( 9 ) and the decreased excretion of carnitine-conjugated metabolites by fenofi brate treatment in humans ( 13 ). Furthermore, an increase in the excretion of glycine conjugated metabolites was observed in Ppara -null mice ( 9 ), and the long-chain fatty acid carnitines, including palmitoylcaritine, myristolcarnitine, oleoylcarnitine, and palmitoleoylcarnitine, were elevated in the serum after suppression of PPAR␣ signal transduction by acetaminophen ( 14 ).…”

Section: Identifi Cation and Quantitation Of Urinary And Serum Metabomentioning

confidence: 99%

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

Patterson

Krausz

et al. 2012

Journal of Lipid Research

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Peroxisome proliferator-activated receptor ␣ (PPAR␣) is a nuclear hormone receptor regulating genes involved in lipid homeostasis, including fatty acid transport and catabolism, lipoprotein metabolism, glucose homeostasis, and infl ammation ( 1, 2 ). Recent studies have suggested a role for PPAR␣ in bile acid biosynthesis. A previous study reported that the expression level of cholesterol 7 ␣ -hydroxylase (Cyp7a1) and 8 ␤ -hydroxylase (Cyp8b1) was upregulated in wild-type mice during [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) treatment and fasting conditions; this effect was diminished in Ppara -null mice, thus revealing the involvement of PPAR␣ ( 3 ). Another study found that both human CYP7A1 and mouse Cyp7a1 promoters were stimulated by fatty acids and Wy-14,643 treatment ( 4 ). These studies provided compelling evidence that PPAR␣ can positively regulate bile acid biosynthesis. In contrast to the above observations, it Abstract Peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) is a nuclear receptor that regulates fatty acid transport and metabolism. Previous studies revealed that PPAR ␣ can affect bile acid metabolism; however, the mechanism by which PPAR ␣ regulates bile acid homeostasis is not understood. In this study, an ultraperformance liquid chromatography coupled with electrospray ionization qua dru pole time-of-fl ight mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics approach was used to profi le metabolites in urine, serum, and bile of wild-type and Ppara -null mice following cholic acid (CA) dietary challenge. Metabolomic analysis showed that the levels of several serum bile acids, such as CA (25-fold) and taurocholic acid (16-fold), were signifi cantly increased in CA-treated Ppara -null mice compared with CA-treated wild-type mice. Phospholipid homeostasis, as revealed by decreased serum lysophos phati dylcholine (LPC) 16:0 (1.6-fold) and LPC 18:0 (1.6-fold), and corticosterone metabolism noted by increased urinary excretion of 11 ␤ -hydroxy-3,20-dioxopregn-4-en-21-oic acid (20-fold) and 11 ␤ ,20 ␣ -dihydroxy-3-oxo-pregn-4-en-21-oic acid (3.6-fold), were disrupted in CA-treated Ppara -null mice. The hepatic levels of mRNA encoding transporters Abcb11, Abcb4, Abca1, Abcg5, and Abcg8 were diminished in Pparanull mice, leading to the accumulation of bile acids in the liver during the CA challenge. These observations revealed that PPAR ␣ is an essential regulator of bile acid biosynthesis, transport, and secretion.

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Metabolomic and Genetic Analysis of Biomarkers for Peroxisome Proliferator-Activated Receptor α Expression and Activation

Cited by 70 publications

References 28 publications

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

Nutrimetabolomics fingerprinting to identify biomarkers of bread exposure in a free-living population from the PREDIMED study cohort

Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

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