Vitamin A5/X, a new food to lipid hormone concept for a nutritional ligand to control RXR-mediated signaling

Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-β,β-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-β,β-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-β,β-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named “Vitamin A5/X”.Université de StrasbourgAgence Nationale de la Recherche (France) | Ref. LabEx ANR-10-LABX-0030-INRTMinisterio de Asuntos Económicos y Transformación Digital (España) | Ref. PID2019-107855RB-I00Xunta de Galicia | Ref. GRC ED431C 2017/61Xunta de Galicia | Ref. ED-431G / 02-FEDE

Ratio of pro-resolving and pro-inflammatory lipid mediator precursors as potential markers for aggressive periodontitis.

Aggressive periodontitis (AgP) is a rapidly progressing type of periodontal disease in otherwise healthy individuals which causes destruction of the supporting tissues of the teeth. The disease is initiated by pathogenic bacteria in the dental biofilm, and the severity of inflammation and attachment loss varies with the host response. Recently, there has been an increased interest in determining the role of lipid mediators in inflammatory events and the concept of pro-inflammatory and pro-resolution lipid mediators has been brought into focus also in periodontal disease. The present study aimed to determine the profile of omega-3 or n3- as well as omega-6 or n6- polyunsaturated fatty acids (PUFAs) and PUFA-metabolites of linoleic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in gingival crevicular fluid (GCF), saliva and serum in AgP patients and healthy controls. In total, 60 selected n3- and n6-PUFAs and various PUFA metabolites were measured using high performance liquid chromatography-tandem electrospray ionisation mass spectrometry (HPLC-ESI-MS-MS). Of these, 51 could be quantified in this study. The concentrations of the majority were low in saliva samples compared with serum and GCF, but were mainly higher in AgP patients compared with healthy controls in all three kinds of sample. Ratios of n3- to n6-PUFAs (DHA + EPA)/AA were significantly lower in the GCF of AgP patients than in the healthy controls. Furthermore, various ratios of the direct precursors of the pro-resolution lipid mediators (precursors of resolvins and protectins) were calculated against the precursors of mainly pro-inflammatory lipid mediators. These ratios were mainly lower in GCF and saliva of AgP patients, compared with healthy controls, but only reached significance in GCF (P<0.05). To conclude, the ratios of precursors of pro-resolution/pro-inflammatory lipid mediators seem to be more relevant for describing the disease status of AgP than the concentration of specific lipid mediators

Vitamin A5/X, a New Food to Lipid Hormone Concept for a Nutritional Ligand to Control RXR-Mediated Signaling

Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-beta,beta-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-beta,beta-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-beta,beta-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named "Vitamin A5/X"

Concentration of lipid mediators in serum samples.

<p>The concentration of lipid mediators in serum of aggressive periodontitis (AgP) patients and healthy controls (HC) was measured by HPLC-MS-MS. Results in ng/ml are expressed as mean ± SD. * Significantly different (<i>P</i><0.05, Mann Whitney test). †Various values below the quantification limit set to 0.05 ng/ml. ** These derivatives may partly origin from autooxidation.</p

Ratio of n3- to n6-PUFAs in gingival crevicular fluid (GCF) (A), saliva (B) and serum (C) samples.

<p>The figure shows the ratios of concentration of (EPA plus DHA) vs. AA in respective fluids of aggressive periodontitis patients (AgP, black bar) and healthy controls (HC, grey bar). * = <i>P</i><0.05 by use of Mann-Whitney test.</p

Concentration of lipid mediators in saliva samples.

<p>The concentration of lipid mediators in saliva of aggressive periodontitis (AgP) patients and healthy controls (HC) was measured by HPLC-MS-MS. Results in ng/ml are expressed as mean ± SD. * Significantly different (<i>P</i><0.05, Mann Whitney test). †Various values below the quantification limit set to 0.02 ng/ml. ** These derivatives may partly origin from autooxidation.</p

Ratios and sums of lipid mediators from GCF – gingivial crevicular fluid, SAL – saliva, SER – serum of aggressive periodontitis (AgP) patients and healthy controls (HC).

<p>Ratios of mono-hydroxylated PUFA metabolites or PUFAs vs. PUFAs; sums of mono-hydroxylated PUFA-metabolites of AA, EPA and DHA and their calculated ratios; summarised metabolites originating from 5-, 12-, 15-LOX and COX metabolic pathways are shown. Data are presented in mean ± sd. * significant different (P<0.05, Mann Whitney test). Numbers in <b>bold</b> indicates increased values while <i>italics</i> indicates reduced values of AgP patients vs. healthy controls.</p

9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice

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9CDHRA is present in mouse serum, brain and liver.

<p>(a) Elution profiles of WT mouse serum (n = 7) and brain (n = 3) samples in comparison with three retinoic acid standards (all-<i>trans</i> [ATRA], 13-<i>cis</i> [13CRA] and 9<i>-cis</i> retinoic acid [9CRA] with retention times 10.4, 9.6, and 9.9 min, respectively) allow identification of ATRA but not 9CRA. Boxes represent areas with comparable retention times to identify co-eluting peaks. (b) 9-<i>cis</i>-13,14-dihydroretinoic acid (9CDHRA; retention time 9.4 min highlighted by dotted-line box) is present in mouse serum (n = 7), brain (n = 3) and liver (n = 7) samples as determined by co-elution with a mixture of 9CDHRA and all-<i>trans</i>-13,14-dihydroretinoic acid (ATDHRA; retention time 9.9 min, highlighted by continuous-line box) standard solution and confirmed by MS-MS (303->207 m/z) and DAD (290 nm) detection. (c) Significant reduction of 9CDHRA, but not ATDHRA levels in serum, brain and liver of <i>Rbp1</i>^{<b><i>-/-</i></b>} animals (n = 8, n = 3 for brain) as compared to WT mice (n = 8, n = 3 for brain). All the error bars represent S.E.M.</p