Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice

Dawson, Paul A.; Gardiner, Brooke; Grimmond, Sean M.; Markovich, Daniel

doi:10.1152/physiolgenomics.00300.2005

Cited by 24 publications

(20 citation statements)

References 55 publications

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“…Our previous study demonstrated increased hepatic sulfotransferase and Sat1 sulfate transporter mRNA levels in Nas1 -/-mice [23], suggesting that sulfotransferase and sulfate transporter mRNA expression is sensitive to changes in blood sulfate levels. In this study we investigated the mRNA expression of two sulfotransferases (Sult1e1 and Hs3st1) and two sulfate transporters (NaS2 and Slc26a2), which are expressed in the placenta [16,17,24,25].…”

Section: Discussionmentioning

confidence: 89%

“…Previously, we showed an altered hepatic transcriptional profile of sulfate transporters and sulfotransferases in Nas1 -/-mice, which we proposed to be a compensatory response to hyposulfataemia [23]. In this study, we quantitated the mRNA levels of two sulfate transporters (Slc13a4 and Slc26a2) and two sulfotransferases (Sult1e1 and Hs3st1), which are normally expressed in mouse placenta [16,17,[24][25], from E12.5 and E18.5 placentae of pregnant Nas1 -/-and Nas1 +/+ mice.…”

Section: Placental Gene Expressionmentioning

confidence: 85%

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Fetal Loss and Hyposulfataemia in Pregnant NaS1 Transporter Null Mice

Dawson

Sim

Simmons

et al. 2011

Journal of Reproduction and Development

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Abstract. Sulfate is important for growth and development, and is supplied from mother to fetus throughout pregnancy. We used NaS1 sulfate transporter null (Nas1 -/-) mice to investigate the role of NaS1 in maintaining sulfate homeostasis during pregnancy and to determine the physiological consequences of maternal hyposulfataemia on fetal, placental and postnatal growth. We show that maternal serum (≤0.5 mM), fetal serum (<0.1 mM) and amniotic fluid (≤0.5 mM) sulfate levels were significantly lower in pregnant Nas1 -/-mice when compared with maternal serum (≈2.0 mM), fetal serum (≈1.5 mM) and amniotic fluid (≈1.7 mM) sulfate levels in pregnant Nas1 +/+ mice. After 12 days of pregnancy, fetal reabsorptions led to markedly reduced (by ≥50%) fetal numbers in Nas1 -/-mice. Placental labyrinth and spongiotrophoblast layers were increased (by ≈140%) in pregnant Nas1 -/-mice when compared to pregnant Nas1 +/+ mice. Birth weights of progeny from female Nas1 -/-mice were increased (by ≈7%) when compared to progeny of Nas1 +/+ mice. These findings show that NaS1 is essential to maintain high maternal and fetal sulfate levels, which is important for maintaining pregnancy, placental development and normal birth weight. Key words: Placenta, Pregnancy, Sulfate (J. Reprod. Dev. 57: [444][445][446][447][448][449] 2011) ulfate (SO4 2-) is vital for many processes in fetal growth and development, including neurogenesis and steroid metabolism [1][2][3]. The ratio of sulfonated (inactive) to unconjugated (active) steroids has important implications for many of the steroid-responsive events that regulate placental and fetal growth [4]. For example, placental estradiol-3-sulfate is taken up by the fetal brain, where it is desulfonated by steroid sulfatase to estradiol, which acts as a potent stimulator of fetal adrenocorticotropin secretion and the hypothalamus-pituitary-adrenal axis [5]. In addition, sulfonation of structural components, such as heparan sulfate proteoglycans (HSPGs), is essential for the maintenance of normal structure and function of placental and fetal tissues [6]. Together, these findings demonstrate an important role for sulfate in maintaining steroid and glycosaminoglycan homeostasis in the developing fetus. SO4 2-is obtained from the diet and from the intracellular metabolism of methionine and cysteine [6]. Circulating SO4 2-levels are maintained by the NaS1 sulfate transporter which is expressed in the kidney where it mediates sulfate reabsorption [7]. During pregnancy, maternal blood sulfate levels increase by approximately 2-fold which provides an essential supply to the placenta and developing fetus [8][9][10][11]. This increase in circulating sulfate level is correlated with increased maternal renal sulfate reabsorption [9,12]. Since the fetus has a relatively low capacity to form sulfate from methionine and cysteine [13,14], most of its sulfate must come from the maternal circulating sulfate pool. These findings are relevant to the decreased fecundity of NaS1 knockout (Nas1 -/-) mice which exhibit bot...

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Section: Discussionmentioning

confidence: 89%

Section: Placental Gene Expressionmentioning

confidence: 85%

Fetal Loss and Hyposulfataemia in Pregnant NaS1 Transporter Null Mice

Dawson

Sim

Simmons

et al. 2011

Journal of Reproduction and Development

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“…By microarray characterization of the changes in hepatic gene expression in NaS1-null mice relative to their wild-type counterparts, Dawson et al (2006) reported that Sult2a expression was increased ;2.0-fold and Sult3a1 was increased ;5.9-fold. These measurements were performed in 4-weekold male mice.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Murine Hepatic Hydroxysteroid Sulfotransferase Expression in Hyposulfatemic Mice and in a Cell Model of 3′-Phosphoadenosine-5′-Phosphosulfate Deficiency

Barrett

Fang

Gargano

et al. 2013

Drug Metabolism and Disposition

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The cytosolic sulfotransferases (SULTs) catalyze the sulfate conjugation of nucleophilic substrates, and the cofactor for sulfonation, 39-phosphoadenosine-59-phosphosulfate (PAPS), is biosynthesized from sulfate and ATP. The phenotype of male knockout mice for the NaS1 sodium sulfate cotransporter includes hyposulfatemia and increased hepatic expression of mouse cytoplasmic sulfotransferase Sult2a and Sult3a1. Here we report that in 8-week-old female NaS1-null mice, hepatic Sult2a1 mRNA levels were ∼51-fold higher than they were in a wild-type liver but expression of no other Sult was affected. To address whether hyposulfatemia-inducible Sult2a1 expression might be due to reduced PAPS levels, we stably knocked down PAPS synthases 1 and 2 in HepG2 cells (shPAPSS1/2 cells). When a reporter plasmid containing at least 233 nucleotides (nt) of Sult2a1 59-flanking sequence was transfected into shPAPSS1/2 cells, reporter activity was significantly increased relative to the activity that was seen for reporters containing 179 or fewer nucleotides.Mutation of an IR0 (inverted repeat of AGGTCA, with 0 intervening bases) nuclear receptor motif at nt 2191 to 180 significantly attenuated the PAPSS1/2 knockdown-mediated increase. PAPSS1/2 knockdown significantly activated farnesoid X receptor (FXR), retinoid-related orphan receptor, and pregnane X receptor responsive reporters, and treatment with the FXR agonist GW4064 [3-(2,6-dichlorophenyl)-4-(39-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole] increased Sult2a1 promoter activity when the IR0 was intact. Transfection of shPAPSS1/2 cells with FXR small interfering RNA (siRNA) significantly reduced the Sult2a1 promoter activity. The impact of PAPSS1/2 knockdown on Sult2a1 promoter activity was recapitulated by knocking down endogenous SULT2A1 expression in HepG2 cells. We propose that hyposulfatemia leads to hepatic PAPS depletion, which causes loss of SULT2A1 activity and results in accumulation of nonsulfated bile acids and FXR activation.

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“…(14)(15)(16)(17) This mouse model provides important insights into the physiological consequences of hyposulfatemia and the function of the NaS1 gene, which is yet to be linked with human disease. These studies are relevant to single nucleotide polymorphisms (R12X and N174S) in the human NaS1 gene, (18) which lead to 100% and 60% loss of function, respectively.…”

mentioning

confidence: 99%

“…(12,13) We generated a NaS1 null (Nas1 ) ⁄ ) ) mouse which exhibits hyposulfatemia, hypersulfaturia, decreased hepatic sulfonation capacity, reduced intestinal sulfomucin content, and decreased circulating dehydroepiandrosterone sulfate (DHEA-S) levels. (14)(15)(16)(17) This mouse model provides important insights into the physiological consequences of hyposulfatemia and the function of the NaS1 gene, which is yet to be linked with human disease. These studies are relevant to single nucleotide polymorphisms (R12X and N174S) in the human NaS1 gene, (18) which lead to 100% and 60% loss of function, respectively.…”

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confidence: 99%

Enhanced tumor growth in the NaS1 sulfate transporter null mouse

et al. 2010

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Sulfate plays an important role in maintaining normal structure and function of tissues, and its content is decreased in certain cancers including lung carcinoma. In this study, we investigated tumor growth in a mouse model of hyposulfatemia (Nas1 ) ⁄ ) ) and compared it to wild-type (Nas1 + ⁄ + ) mice. Lung epithelial tumor cells (TC-1 cell line) were injected subcutaneously into male Nas1and Nas1 + ⁄ + mice on a mixed 129Sv and C57BL ⁄ 6 genetic background. Tumor sections were stained with anti-glycosaminoglycan antibodies to assess the distribution of proteoglycans and Gomori's trichrome to detect collagen. After 14 days, tumor weights were markedly increased (by 12-fold) in Nas1) ⁄ ) mice when compared with Nas1 + ⁄ + mice. Histological analyses of tumors revealed increased (by 2.4-fold) vessel content, as well as markedly reduced collagen and immunoreactivity against glycosaminoglycan structural epitopes in the tumors from Nas1 ) ⁄ ) mice. No significant differences were found for the growth of cultured TC-1 cells supplemented with Nas1) ⁄ ) or Nas1 + ⁄ + serum, as determined by 3 H-thymidine incorporation, implying that the cell culture conditions may not reflect the in vivo situation of enhanced tumor growth. This study has revealed increased tumor growth and an altered extracellular tumor matrix in hyposulfatemic Nas1) ⁄ ) mice. These findings highlight the importance of blood sulfate levels as a possible modulator of tumor growth, and could lead to future cancer studies in humans with altered sulfate homeostasis. (Cancer Sci 2010; 101: 369-373) S ulfate (SO 4 2) ) is an abundant anion in the human body and is essential for numerous cellular and metabolic processes.(1) SO 4 2) conjugation or sulfonation of glycosaminoglycans (GAGs) is important for maintaining the structure and function of tissues.(2) Heparan sulfate proteoglycans (HSPGs) are a group of variably sulfonated GAGs found at the cell surface and extracellular matrix, which play a major role in regulating growth factor signaling in tumors.(3) In particular, the sulfate content of HSPGs is a critical factor in modulating tumor growth and angiogenesis.(4) Desulfonation of HSPGs by sulfatases promotes the release of growth factors that enhance tumor growth, (5) and increased sulfatase activity is associated with a poor prognosis in patients with hepatocellular carcinoma, breast, and pancreatic cancers. (6)(7)(8) In addition, the removal of highly sulfonated regions of HSPGs, using heparanase I, leads to accelerated tumor growth, neovascularization, and decreased apoptosis in a mouse model of lung carcinoma.(3) Highly sulfonated HSPGs or heparins, as well as sulfonated polymers such as laminarin sulfate, act as inhibitors of heparanase activity and have beneficial outcomes in preventing tumor growth and angiogenesis in vivo.(9) These studies highlight the importance of sulfate in modulating tumor growth and angiogenesis. SO 4 2) is obtained directly from the diet and from the oxidation of sulfur containing amino acids, methionine and cysteine....

show abstract

Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice

Cited by 24 publications

References 55 publications

Fetal Loss and Hyposulfataemia in Pregnant NaS1 Transporter Null Mice

Fetal Loss and Hyposulfataemia in Pregnant NaS1 Transporter Null Mice

Regulation of Murine Hepatic Hydroxysteroid Sulfotransferase Expression in Hyposulfatemic Mice and in a Cell Model of 3′-Phosphoadenosine-5′-Phosphosulfate Deficiency

Enhanced tumor growth in the NaS1 sulfate transporter null mouse

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