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It has recently been reported that carriers of the less common allele at the scavenger receptor class B type I (SR-BI) exon 1 polymorphism are more susceptible to the presence of saturated fatty acid in the diet because of a greater increase in LDL cholesterol. Our aim was to determine if this polymorphism could also influence postprandial lipoprotein metabolism, because the SR-BI has been described as a possible mediator in the intestinal absorption of triacylglycerols. Forty-seven normolipidemic volunteers who were homozygous for the E3 allele at the APOE gene were selected [37 homozygous for the common genotype (1/1) at the SR-BI exon 1 polymorphism and 10 heterozygous (1/2)]. They were given a fat-rich meal containing 1 g fat and 7 mg cholesterol per kg body weight and vitamin A 60,000 IU/m2 body surface. Fat accounted for 60% of calories, and protein and carbohydrates accounted for 15% and 25% of energy respectively. Blood samples were taken at time 0, every 1 h until 6 h, and every 2.5 h until 11 h. Total cholesterol and triacylglycerols in plasma, and cholesterol, triacylglycerols and retinyl palmitate in triacylglycerol-rich lipoproteins (large and small triacylglycerol-rich lipoproteins) were determined. Postprandial responses for triacylglycerols and retinyl palmitate in small triacylglycerol-rich lipoproteins were higher in 1/1 individuals than in 1/2 individuals. No other significant differences were noted. Our data show that the presence of the genotype 1/2 is associated with a lower postprandial lipemic response.
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ABSTRACT
Although the kidney and intestine are among the major organs involved in both the biotransformation and action of vitamin D3, they exhibit very distinct roles in calcium and D3 homeostasis. The aim of the present studies was to investigate the relative in vivo responsiveness of renal and intestinal 1,25(OH)2D3-24-hydroxylase (24-hydroxylase) mRNA levels to calcitriol (1,25(OH)2D3) following acute or chronic 1,25(OH)2D3 exposure using hypocalcemic vitamin D-depleted rats as an experimental model. Intestinal 24-hydroxylase mRNA levels were very responsive to a single i.v. injection of 2·4, 12 or 120nmol 1,25(OH)2D3/kg but in kidney the mRNA levels only increased following exposure to the highest 1,25(OH)2D3 concentration, and exhibited a maximum response only 30% of that in the intestine despite similar tissue uptake of the hormone. To evaluate whether the kidney might preferentially respond to endogenously produced 1,25(OH)2D3, animals received increasing doses of 25(OH)D3. Although the intestinal 24-hydroxylase transcript was highly induced, the renal transcript was unresponsive to 25(OH)D3 treatment despite circulating 1,25(OH)2D3 concentrations of 24 nmol/l. By contrast, intestinal 24-hydroxylase mRNA levels were largely unresponsive to long-term calcitriol administration while the renal transcript, although insensitive to a physiological dose, responded to pharmacological 1,25(OH)2D3 doses. However, when challenged acutely with 1,25(OH)2D3 following chronic exposure, the kidney 24-hydroxylase mRNA levels remained largely unresponsive in contrast to the intestinal transcript which was markedly induced. These data indicate that significant differences exist in the in vivo tissue responsiveness of the 24-hydroxylase mRNA. Indeed, the gene exhibited high intestinal responsiveness to acutely, but not chronically, administered 1,25(OH)2D3, while in the kidney it only responded to high exogenous 1,25(OH)2D3 delivered either acutely or chronically. In addition, these site-specific regulatory mechanisms governing the expression of the 24-hydroxylase gene are independent of the endocrine calcium status and render the kidney relatively resistant to endogenously produced 1,25(OH)2D3.
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The type 1 parathyroid hormone receptor (PTHR1) binds, with equal affinity, two ligands with distinct biological functions: PTH, the major peptide hormone controlling calcium homeostasis, and the paracrine factor, PTH-related peptide (PTHrP), a local regulator of cellular proliferation and differentiation. To clarify the complexity of possible interactions between two distinct ligands, PTH and PTHrP, and their common receptor in the intact organism, and to identify as yet unrecognized roles for PTH in normal physiology, we have cloned and characterized the structural organization, nucleotide sequence and transcriptional regulation of the murine gene encoding PTH. One recombinant clone isolated from a mouse genomic library contained 14 kb of DNA, encompassing the entire Pth gene. The transcriptional unit spans 3.2 kb of genomic DNA and, analogous to the human PTH gene, it is interrupted by two introns. The deduced mRNA encodes the 115-amino acid precursor, preproPTH. Comparison of the murine preproPTH sequence with other mammalian forms of the protein shows it to be highly conserved and to share limited structural similarity to PTHrP at the amino-terminal region, a domain critical for binding and activation of their common receptor. Putative binding motifs for the transcription factors sex-determining region Y gene product, transcriptional repressor CDP, hepatic nuclear factor 3beta, GATA-binding factor 1, glucocorticoid receptor, SRY-related high mobility group box protein 5 and cAMP response element binding protein were identified in the 5' flanking region of the Pth gene. When placed upstream of a reporter gene, these sequences failed to confer transcriptional regulation in response to 1,25(OH)(2) vitamin D(3), but responded positively to the addition of isoproterenol and forskolin. Mutational analysis identified a cAMP-response element in the Pth promoter.
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Critical to an understanding of the control of 1,25-dihydroxyvitamin D (1,25D) activity is a molecular appreciation of the regulation of three genes, 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1), 25-hydroxyvitamin D-24-hydroxylase (CYP24) and vitamin D receptor (VDR). We now report the sensitivity, reproducibility and accuracy of a real-time reverse transcriptase-polymerase chain reaction protocol (Taqman) for the quantification of mRNA levels for these genes in total RNA extracted from kidney tIssue. The sensitivity of the protocol was at least 150 copies of mRNA per reaction. Reproducibility, expressed as the coefficient of variation, ranged between 14 and 30% at the level of approximately 10(4) copies of mRNA per reaction. Accuracy was estimated at greater than 95% for each of these mRNAs. This protocol allows for the comparison of absolute mRNA levels in extracted total RNA in kidneys from animals fed diets containing different levels of calcium, ranging from 0.05% to 1%. Serum 1,25D levels were decreased when the dietary calcium concentration was increased (P<0.05). The levels of CYP27B1 mRNA were highest in the animals fed the 0.05% calcium diet (P<0.01). Conversely, CYP24 and VDR mRNA levels were highest in the animals fed the 1% calcium diet (P<0.01). Both CYP27B1 and CYP24 mRNA levels were major determinants of serum 1,25D levels when dietary calcium intakes were varied in these adult animals (Multiple R(2)=0.70, P<0.01). No significant relationship was detected between kidney CYP27B1 and serum parathyroid hormone (PTH) suggesting that serum calcium may regulate CYP27B1 mRNA expression directly during normocalcaemia. Low levels of CYP24 mRNA were associated with high PTH levels. These findings suggest that kidney CYP24 activity, possibly regulated by factors such as PTH, acts in concert with kidney CYP27B1 to control serum 1,25D levels.
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From a database containing the published nuclear hormone receptor (NR) sequences I constructed an alignment of the C, D and E domains of these molecules. Using this alignment, I have performed tree reconstruction using both distance matrix and parsimony analysis. The robustness of each branch was estimated using bootstrap resampling methods. The trees constructed by these two methods gave congruent topologies. From these analyses I defined six NR subfamilies: (i) a large one clustering thyroid hormone receptors (TRs), retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), vitamin D receptors (VDRs) and ecdysone receptors (EcRs) as well as numerous orphan receptors such as RORs or Rev-erbs; (ii) one containing retinoid X receptors (RXRs) together with COUP, HNF4, tailless, TR2 and TR4 orphan receptors; (iii) one containing steroid receptors; (iv) one containing the NGFIB orphan receptors; (v) one containing FTZ-F1 orphan receptors; and finally (vi) one containing to date only one gene, the GCNF1 orphan receptor. The relationships between the six subfamilies are not known except for subfamilies I and IV which appear to be related. Interestingly, most of the liganded receptors appear to be derived when compared with orphan receptors. This suggests that the ligand-binding ability of NRs has been gained by orphan receptors during the course of evolution to give rise to the presently known receptors. The distribution into six subfamilies correlates with the known abilities of the various NRs to bind to DNA as homo- or heterodimers. For example, receptors heterodimerizing efficiently with RXR belong to the first or the fourth subfamilies. I suggest that the ability to heterodimerize evolved once, just before the separation of subfamilies I and IV and that the first NR was able to bind to DNA as a homodimer. From the study of NR sequences existing in vertebrates, arthropods and nematodes, I define two major steps of NR diversification: one that took place very early, probably during the multicellularization event leading to all the metazoan phyla, and a second occurring later on, corresponding to the advent of vertebrates. Finally, I show that in vertebrate species the various groups of NRs accumulated mutations at very different rates.
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There is mounting evidence that vitamin D and its metabolites play important roles in regulating plasma calcium concentrations in teleost fish as in other vertebrates. The aims of the present study were to elucidate the possible cellular target mechanisms for the rapid actions of 24R,25(OH)(2)D(3), 25(OH)D(3) and 1,25(OH)(2)D(3) in Atlantic cod enterocytes at physiological doses, and to establish the concentration and thus the physiological range of circulating 24R,25(OH)(2)D(3), 25(OH)D(3) and 1,25(OH)(2)D(3) in the Atlantic cod. The plasma concentrations of 25(OH)D(3), 1,25(OH)(2)D(3) and 24R,25(OH)(2)D(3) were 15.3 +/- 2.7nM, 125.1 +/- 12.3pM and 10.1 +/- 23.5nM respectively. Exposure of enterocytes to 10mM calcium (Ca(2+)) evoked an increase in intracellular Ca(2+) concentrations ([Ca(2+)](i)). This increase was suppressed by 24R,25(OH)(2)D(3) dose-dependently, with an EC(50) of 4.9nM and a maximal inhibition of 60%. 24R,25(OH)(2)D(3) (20nM) abolished an increase in [Ca(2+)](i) (approximately 252%) in the control enterocytes exposed to 10microM S(-)-BAYK-8644, suggesting that the hormone acts by inhibiting Ca(2+) entry through L-type voltage-gated Ca(2+) channels. Administration of 20nM 24R,25(OH)(2)D(3) to enterocytes in the absence of extracellular Ca(2+) increased [Ca(2+)](i) by approximately 20%, indicating a release of Ca(2+) from intracellular stores. Administration of 25(OH)D(3) (20nM) resulted in a biphasic change in the enterocyte [Ca(2+)](i): within 1--5s, it decreased to 87 +/- 12nM below its mean basal [Ca(2+)](i) (334 +/- 13nM), followed by a rapid recovery of [Ca(2+)](i) to a new level, 10% lower than the initial [Ca(2+)](i). The rapid decrease, the recovery rate and the final [Ca(2+)](i) were all affected dose-dependently by 25(OH)D(3), with EC(50) values of 8.5, 17.0 and 18.9nM respectively. Furthermore, the effects of 25(OH)D(3) were sensitive to sodium (Na(+)), bepridil (10microM) and nifedipine (5 microM), suggesting that 25(OH)D(3) regulates the activity of both basolateral membrane-associated Na(+)/Ca(2+) exchangers and brush border membrane-associated L-type Ca(2+) channels. Administration of 25(OH)D(3) (10nM) to enterocytes in the absence of extracellular Ca(2+) increased [Ca(2+)](i) by approximately 18%, indicating a release of Ca(2+) from intracellular stores. 1,25(OH)(2)D(3) also affected enterocyte [Ca(2+)](i) in a biphasic manner: the rapid decrease, the recovery rate, and the mean final [Ca(2+)](i) were all affected dose-dependently, with EC(50) values of 8.3, 24.5 and 7.7nM respectively. The high EC(50) values for 1,25(OH)(2)D(3) compared with circulating concentrations of 1,25(OH)(2)D(3) (130pM) suggest that this effect is pharmacological, rather than of physiological relevance in enterocyte Ca(2+) homeostasis of the Atlantic cod. It is concluded that 24R,25(OH)(2)D(3) has a physiological role in decreasing intestinal Ca(2+) uptake via inactivation of L-type Ca(2+) channels, whereas the physiological role of 25(OH)D(3) is to increase enterocyte Ca(2+) transport via activation of Na(+)/Ca(2+) exchangers, concurrent with activation of L-type Ca(2+) channels.
Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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Service de Biochimie de l’Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, Place Amélie Raba Léon, 33000 Bordeaux, France
Service d’Endocrinologie, Diabétologie et Maladies Métaboliques de l’Hôpital Haut-Levêque, Centre Hospitalier Universitaire de Bordeaux, Avenue Magellan, 33600 Pessac, France
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target genes in response to RA (retinoic acid) ligand (RA is the active form of vitamin A) ( Marill et al. 2003 ). Vitamin A, via RA, exerts a wide variety of profound effects on growth, tissue differentiation and homeostasis ( Sporn et al. 1994
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that have been identified by functional investigations to have a role in the regulation of the immune response. The vitamin D-endocrine axis has a well-established influence on immune-system function ( DeLuca & Cantorna 2001 ). Administration of 1
Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran
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. 2020 Hypovitaminosis D Fatigue Generalized weakness Arthritis Reduced serum vitamin D Reduced serum Ca N/A 612,601 (systematic review) Decreased vitamin was associated with increased risk of infection and severity of COVID-19 Petrelli
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spermatogonial differentiation and how the action of vitamin A on this process and on the organization of spermatogenesis in time and space is critical for normal continual sperm production. Organization of the testis The seminiferous epithelium of
