Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats

Lysne, Vegard; Strand, Elin; Svingen, Gard Frodahl Tveitevåg; Bjørndal, Bodil; Pedersen, Eva Ringdal; Midttun, Øivind; Olsen, Trond E.; Ueland, Per Magne; Berge, Rolf K.; Nygård, Ottar

doi:10.3390/nu8010026

Cited by 17 publications

(28 citation statements)

References 72 publications

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“…117 Treatment of healthy individuals with fibrates (PPARA-agonists) results in increased urinary choline and betaine, 118 with similar findings in animal models. 119 Our urinary observations support our proteomic and gene level findings which together suggest that the alterations observed in NEVKP-treated kidneys may reflect increased PPARA and PPARGC1A activity.…”

Section: Discussionsupporting

confidence: 87%

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

McEvoy

Clotet-Freixas

Tokár

et al. 2020

Preprint

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Normothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid β-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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Section: Discussionsupporting

confidence: 87%

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

McEvoy

Clotet-Freixas

Tokár

et al. 2020

Preprint

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“…Another limitation of this assay lies in its unreliability to reflect cellular vitamin B 12 status. Results from studies assessing serum and cellular vitamin B 12 have shown that the levels of serum B 12 do not always represent cellular B 12 status (Carmel, 2000 ; Solomon, 2005 ; Devalia et al, 2014 ; Lysne et al, 2016 ). In particular, patients with inborn errors of vitamin B 12 metabolism can present with normal or low serum values of the vitamin, while being deficient at the cellular level.…”

Section: Serum Biomarkers Of Vitamin B 12 Deficienmentioning

confidence: 99%

“…A number of studies point to the lack of correlation between serum and cellular levels of vitamin B 12 (Carmel, 2000 ; Solomon, 2005 ; Devalia et al, 2014 ; Lysne et al, 2016 ), and this is particularly important in the case of inborn errors of cobalamin metabolism whereby serum levels of the micronutrient are within the normal range(Watkins and Rosenblatt, 2013 ). In this regard, serum vitamin B 12 and holo-TC should be avoided as sole markers of B 12 deficiency in neonatal screening.…”

Section: Challenges In the Diagnosis Of Vitamin B 12 mentioning

confidence: 99%

“…Upregulation of the expression of hepatic peroxisome proliferator activated receptor alpha (PPAR alpha), has been shown to elevate plasma MMA in male Wistar rats fed a normal high fat diet in the presence of PPAR alpha agonist tetradecylthioacetic acid (TTA) (Lysne et al, 2016 ). Because the amount of receptor is a limiting factor for PPAR alpha activity, and the amount of PPAR alpha protein strongly correlates with its level of mRNA expression (Lemberger et al, 1996 ), differential expression of PPAR alpha induced by diet, stress and other factors may represent another vitamin B 12 -independent determinant of plasma MMA.…”

Section: Genetic Determinants Of Vitamin B 12 Statmentioning

confidence: 99%

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Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency

Hannibal

Lysne

Bjørke‐Monsen

et al. 2016

Front. Mol. Biosci.

Self Cite

236

254

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Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.

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“…An elusive aspect of vitamin B 12 metabolism concerns the lack of a distinct correlation between serum and tissue levels of the micronutrient (47)(48)(49)(50) and an unclarified role of the vascular endothelium in that homeostasis. We have previously shown that bovine aortic endothelial cells (BAECs) can take up and process Cbl to generate the 2 cofactors MeCbl and AdoCbl (27,51).…”

mentioning

confidence: 99%

Transcellular transport of cobalamin in aortic endothelial cells

et al. 2018

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Cobalamin [Cbl (or B)] deficiency causes megaloblastic anemia and a variety of neuropathies. However, homeostatic mechanisms of cyanocobalamin (CNCbl) and other Cbls by vascular endothelial cells are poorly understood. Herein, we describe our investigation into whether cultured bovine aortic endothelial cells (BAECs) perform transcytosis of B, namely, the complex formed between serum transcobalamin and B, designated as holo-transcobalamin (holo-TC). We show that cultured BAECs endocytose [Co]-CNCbl-TC (source material) via the CD320 receptor. The bound Cbl is transported across the cell both via exocytosis in its free form, [Co]-CNCbl, and via transcytosis as [Co]-CNCbl-TC. Transcellular mobilization of Cbl occurred in a bidirectional manner. A portion of the endocytosed [Co]-CNCbl was enzymatically processed by methylmalonic aciduria combined with homocystinuria type C (cblC) with subsequent formation of hydroxocobalamin, methylcobalamin, and adenosylcobalamin, which were also transported across the cell in a bidirectional manner. This demonstrates that transport mechanisms for Cbl in vascular endothelial cells do not discriminate between various β-axial ligands of the vitamin. Competition studies with apoprotein- and holo-TC and holo-intrinsic factor showed that only holo-TC was effective at inhibiting transcellular transport of Cbl. Incubation of BAECs with a blocking antibody against the extracellular domain of the CD320 receptor inhibited uptake and transcytosis by ∼40%. This study reveals that endothelial cells recycle uncommitted intracellular Cbl for downstream usage by other cell types and suggests that the endothelium is self-sufficient for the specific acquisition and subsequent distribution of circulating B via the CD320 receptor. We posit that the endothelial lining of the vasculature is an essential component for the maintenance of serum-tissue homeostasis of B.-Hannibal, L., Bolisetty, K., Axhemi, A., DiBello, P. M., Quadros, E. V., Fedosov, S., Jacobsen, D. W. Transcellular transport of cobalamin in aortic endothelial cells.

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Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats

Cited by 17 publications

References 72 publications

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency

Transcellular transport of cobalamin in aortic endothelial cells

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