Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)

Bartolini, Desirée; Torquato, Pierangelo; Barola, Carolina; Russo, Angelo; Rychlicki, C.; Giusepponi, Danilo; Bellezza, Guido; Sidoni, Angelo; Galarini, Roberta; Svegliati‐Baroni, Gianluca; Galli, Francesco

doi:10.1016/j.jnutbio.2017.06.003

Cited by 44 publications

(37 citation statements)

References 72 publications

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“…Remarkable are also the consistent outcomes of clinical studies addressing the therapeutic potential of vitamin E in NAFLD with manifestation of the metabolic syndrome 6 , 7 , because LCMs are strikingly enriched in liver upon oral administration of vitamin E as shown for γ-T ( 1c ) in rats 28 . Moreover, metabolic dysregulations that promote NAFLD led to reduced hepatic expression of CYP4F2, the initial enzyme in LCM biosynthesis, in a high fat murine model of steatosis 46 , and to lower excretion of vitamin E metabolites by patients with metabolic syndrome 47 . In consequence, the progression from healthy liver to non-alcoholic steatohepatitis is accompanied by enhanced 5-LO product levels 48 , and deletion of 5-LO has (i) anti-steatotic, anti-inflammatory, and anti-fibrotic effects in experimental models of liver disease 49 , (ii) protects from hepatic inflammatory injury, and (iii) improves insulin signaling at high-fat diet 14 .…”

Section: Discussionmentioning

confidence: 99%

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

Pein¹,

Ville²,

Pace³

et al. 2018

Nat Commun

116

139

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Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.

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Section: Discussionmentioning

confidence: 99%

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

Pein¹,

Ville²,

Pace³

et al. 2018

Nat Commun

116

139

View full text Add to dashboard Cite

show abstract

“…Cattle with lower expression of cutaneous CYP4F3, another CYP450 which metabolizes LTB4, also show resistance to ectoparasites by maintaining greater amounts of LTB4 (Tabor et al, 2017). Differential expression of CYP4F2 may also alter the rate of degradation of vitamin E. Certainly in other species, reduced expression of CYP4F2 slows the breakdown of vitamin E; however, the contribution of CYP4F2 to circulating vitamin E concentrations in cattle is unknown (Bartolini et al, 2017). The lack of consistent expression of TCωH CYP4F2 and CYP4A11 cell culture models underscores why such research is so difficult to undertake.…”

Section: ω-Hydroxylasesmentioning

confidence: 99%

Widespread basal cytochrome P450 expression in extrahepatic bovine tissues and isolated cells

Kühn

Putman

Sordillo

2020

Journal of Dairy Science

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Periparturient cattle face increased risk of both metabolic and infectious diseases. Factors contributing to this predisposition include oxidized polyunsaturated fatty acids, also known as oxylipids, whose production is altered during the periparturient period and in diseased cattle. Alterations in the production of oxylipids derived from cytochrome P450 (CYP450) enzymes are over-represented during times of increased disease risk and clinical disease, such as mastitis. Many of these same CYP450 enzymes additionally regulate metabolism of fat-soluble vitamins, such as A, D, and E. These vitamins are essential to maintaining immune health, yet circulating concentrations are diminished near calving. Despite this, a relatively small amount of research has focused on the roles of CYP450 enzymes outside of the liver. The aim of this paper is to describe the relative gene expression of 11 CYP450 in bovine tissues and common in vitro bovine cell models. Eight tissue samples were collected from 3 healthy dairy cows after euthanasia. In vitro samples included primary bovine aortic and mammary endothelial cells and immortalized bovine kidney and mammary epithelial cells. Quantitative real-time-PCR was carried out to assess basal transcript expression of CYP450 enzymes. Surprisingly, CYP450 mRNA was widely expressed in all tissue samples, with predominance in the liver. In vitro CYP450 expression was less robust, with several cell types lacking expression of specific CYP450 enzymes altogether. Overall, cell culture models did not reflect expression of tissue CYP450. However, when CYP450 were organized by activity, certain cell types consistently expressed specific functional groups. These data reveal the widespread expression of CYP450 in individual organs of healthy dairy cows. Widespread expression helps to explain previous evidence of significant changes in CYP450-mediated oxylipid production and fat-soluble vitamin metabolism in organ microenvi-ronments during periods of oxidative stress or disease. As such, these data provide a foundation for targeted functional experiments aimed at understanding the activities of specific CYP450 and associated therapeutic potential during times of increased disease risk.

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“…Vitamin E catabolism produces a short‐chain metabolite 2,5,7,8‐tetramethyl‐2(2α‐carboxyethyl)‐6‐hydroxychroman (α‐CEHC) and long‐chain metabolites with regulatory functions on cellular lipids as cyclooxygenase inhibitors or 5‐lipoxygenase inhibitors . Analysis protocols have been developed to measure vitamin E metabolites that have been utilized in the study of vitamin E metabolism in healthy subjects and in pathologic conditions . The extrapolation of the in vitro effects to in vivo physiological situations deserves further investigations.…”

Section: Toward a Molecular Understanding Of The Mechanisms Involved mentioning

confidence: 99%

Vitamin E – The Next 100 Years

Khadangi

Azzi

2018

IUBMB Life

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α‐Tocopherol is the only tocopherol that has been shown to prevent the human deficiency disease Ataxia with Isolated Vitamin E Deficiency (AVED), and thus it is the only one that, for humans, can be called vitamin E. Vitamin E in addition to preventing AVED has documented immune boosting properties and an activity against nonalcoholic hepatosteatosis and low‐grade inflammation. Epidemiological studies indicating that vitamin E could prevent cardiovascular events, neurodegenerative disease, macular degeneration, and cancer were in general not confirmed by clinical intervention studies. Vitamin E and some of its metabolites modulate cell signaling and gene transcription. Future research is needed to achieve a better understanding of the molecular events leading to gene regulation by vitamin E, especially in its phosphorylated form. Isolation and characterization of the vitamin E kinase and vitamin E phosphate phosphatase will help in the understanding of cell regulation processes modulated by vitamin E. A clarification of the pathogenesis of AVED remains an important goal to be achieved. © 2018 IUBMB Life, 71(4):411–415, 2019

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Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)

Cited by 44 publications

References 72 publications

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

Widespread basal cytochrome P450 expression in extrahepatic bovine tissues and isolated cells

Vitamin E – The Next 100 Years

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