The intestinal metal transporter ZIP14 maintains systemic manganese homeostasis

Scheiber, Ivo F.; Wu, Yuze; Morgan, Shannon E.; Zhao, Ningning

doi:10.1074/jbc.ra119.008762

Cited by 60 publications

(82 citation statements)

References 52 publications

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“…The iron transporters SLC11A2 and SLC40A1 may contribute to this absorption process, however data supporting a critical role are lacking (7)(8)(9)(10)(11)(12)14). In intestinal enterocytes, SLC39A14 at the basolateral membrane and SLC30A10 at the apical membrane limit Mn absorption and/or enhance intestinal Mn excretion (15,16). Once absorbed, Mn is transported to the liver for distribution to other tissues, storage, or use within liver, or excreted from the body.…”

Section: Discussionmentioning

confidence: 99%

“…The metal importer SLC39A14 (also known as ZIP14) and exporter SLC30A10 (also known as ZNT10) have been implicated in Mn transport across the intestines. In cell culture, SLC39A14 mediates basolateral-to-apical/secretory Mn transport, and deficiency in SLC39A14 enhances Mn transport in the apical-to-basolateral/absorptive direction (15). Studies in mice with endoderm-specific Slc30a10 deficiency and mice with intestine-specific Slc39a14 deficiency suggest that intestinal Slc30a10 and Slc39a14 regulate systemic Mn levels (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…In cell culture, SLC39A14 mediates basolateral-to-apical/secretory Mn transport, and deficiency in SLC39A14 enhances Mn transport in the apical-to-basolateral/absorptive direction (15). Studies in mice with endoderm-specific Slc30a10 deficiency and mice with intestine-specific Slc39a14 deficiency suggest that intestinal Slc30a10 and Slc39a14 regulate systemic Mn levels (15,16). Once absorbed, Mn may be imported into cells by SLC11A2 and other transporters including SLC39A8 (also known as ZIP8), SLC39A14, and the transferrin receptor (17).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity

Mercadante¹,

Prajapati²,

Conboy³

et al. 2019

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity

Mercadante¹,

Prajapati²,

Conboy³

et al. 2019

Journal of Clinical Investigation

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“…The Divalent Metal Transporter 1 (DMT1, encoded by SLC11A2) transports Mn from the intestinal lumen into enterocytes (31). SLC39A14 takes up Mn from the basolateral side of enterocytes (50), and it has been reported that SLC39A14 acts synergistically with SLC30A10 to mediate whole-body Mn excretion (50)(51)(52). However we found that BA treatments had no effects on Slc11a2 or Slc39a14 expression in murine organoids (Fig.…”

Section: Effects Of Ba Composition On Other Mn Transportersmentioning

confidence: 74%

Bile acid composition regulates the manganese transporter Slc30a10 in intestine

Ahmad

Higuchi

Bertaggia

et al. 2020

Preprint

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“…Other hallmarks include iron depletion and hyperbilirubinemia. Mendelian disorders of SLC30A10 and the other hepatic Mn transporter genes SLC39A8 (solute carrier family 39 member 8, causing 56 , along with experiments in transgenic mice57,58 , have confirmed the critical role of each of these genes in maintaining whole-body manganese homeostasis59 . Notably, while all three of the genes have Mendelian syndromes with neurological manifestations, only SLC30A10 deficiency (HMNDYT1) is known to be associated with liver disease 59 .…”

mentioning

confidence: 90%

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

Ward

Quenneville

et al. 2020

Preprint

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22To better understand molecular pathways underlying liver health and disease, we performed 23 genome-wide association studies (GWAS) on circulating levels of alanine aminotransferase (ALT) 24 and aspartate aminotransferase (AST) across 408,300 subjects from four ethnic groups in the UK 25 Biobank, focusing on variants associating with both enzymes. Of these variants, the strongest 26 effect is a rare (MAF in White British = 0.12%) missense variant in the gene encoding manganese 27 efflux transporter SLC30A10, Thr95Ile (rs188273166), associating with a 5.9% increase in ALT 28 and a 4.2% increase in AST. Carriers have higher prevalence of all-cause liver disease (OR = 1.70; 29 95% CI = 1.24 to 2.34) and higher prevalence of extrahepatic bile duct cancer (OR = 23.8; 95% 30 CI = 9.1 to 62.1) compared to non-carriers. Over 4% of the cases of extrahepatic 31 cholangiocarcinoma in the UK Biobank carry SLC30A10 Thr95Ile. Unlike variants in SLC30A10 32 known to cause the recessive syndrome hypermanganesemia with dystonia-1 (HMNDYT1), the 33 Thr95Ile variant has a detectable effect even in the heterozygous state. Also unlike HMNDYT1-34 causing variants, Thr95Ile results in a protein that is properly trafficked to the plasma membrane 35 when expressed in HeLa cells. These results suggest that coding variation in SLC30A10 impacts 36 liver health in more individuals than the small population of HMNDYT1 patients. 37 are sensitive biomarkers of liver injury; in particular, alanine aminotransferase (ALT) and aspartate 44 aminotransferase (AST) are released into the circulation during damage to hepatocyte 45 membranes 1,2 . One powerful approach for understanding the molecular basis of liver disease has 46 been to perform genome-wide association studies (GWAS) of levels of circulating liver enzymes 47 across large population samples 1,3-13 . Combined GWAS of ALT and AST have previously revealed 48 genetic associations providing potential therapeutic targets for liver disease such as PNPLA3 14 and 49HSD17B13 15 . To further study the genetics of hepatocellular damage, we performed GWAS on 50 circulating levels of ALT and AST in 408,300 subjects, meta-analyzed across four ethnic groups 51 in the UK Biobank. 52 Results 53 GWAS summary 54We performed a GWAS of ALT and AST in four sub-populations in the UK Biobank (Asian or 55 Asian British, Black or Black British, Chinese, and Black or Black British; sample sizes, number 56 of variants tested, and lGC values, Supplementary Table 1; genome-wide significant associations, 57 Supplementary Table 2; Manhattan and QQ plots for each enzyme and sub-population, 58 Supplementary Figures 1 and 2). After meta-analyzing across sub-populations to obtain a single 59 set of genome-wide p-values for each enzyme (Manhattan plots, Figure 1), we found 244 and 277 60 independent loci associating at p < 5 x 10 -8 with ALT and AST, respectively, defined by lead SNPs 61 separated by at least 500 kilobases and pairwise linkage disequilibrium (LD) r 2 less than 0.2. 62Enzyme levels were strongly associated w...

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The intestinal metal transporter ZIP14 maintains systemic manganese homeostasis

Cited by 60 publications

References 52 publications

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity

Manganese transporter Slc30a10 controls physiological manganese excretion and toxicity

Bile acid composition regulates the manganese transporter Slc30a10 in intestine

GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms

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