Whittamore Jonathan M, Hatch Marguerite
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida
Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida.
Am J Physiol Gastrointest Liver Physiol. 2017 Sep 1;313(3):G166-G179. doi: 10.1152/ajpgi.00079.2017. Epub 2017 May 19.
The ileum is considered the primary site of inorganic sulfate ([Formula: see text]) absorption. In the present study, we explored the contributions of the apical chloride/bicarbonate (Cl/[Formula: see text]) exchangers downregulated in adenoma (DRA; Slc26a3), and putative anion transporter 1 (PAT1; Slc26a6), to the underlying transport mechanism. Transepithelial [Formula: see text] and Cl fluxes were determined across isolated, short-circuited segments of the distal ileum from wild-type (WT), DRA-knockout (KO), and PAT1-KO mice, together with measurements of urine and plasma sulfate. The WT distal ileum supported net sulfate absorption [197.37 ± 13.61 (SE) nmol·cm·h], but neither DRA nor PAT1 directly contributed to the unidirectional mucosal-to-serosal flux ([Formula: see text]), which was sensitive to serosal (but not mucosal) DIDS, dependent on Cl, and regulated by cAMP. However, the absence of DRA significantly enhanced net sulfate absorption by one-third via a simultaneous rise in [Formula: see text] and a 30% reduction to the secretory serosal-to-mucosal flux ([Formula: see text]). We propose that DRA, together with PAT1, contributes to [Formula: see text] by mediating sulfate efflux across the apical membrane. Associated with increased ileal sulfate absorption in vitro, plasma sulfate was 61% greater, and urinary sulfate excretion () 2.2-fold higher, in DRA-KO mice compared with WT controls, whereas was increased 1.8-fold in PAT1-KO mice. These alterations to sulfate homeostasis could not be accounted for by any changes to renal sulfate handling suggesting that the source of this additional sulfate was intestinal. In summary, we characterized transepithelial sulfate fluxes across the mouse distal ileum demonstrating that DRA (and to a lesser extent, PAT1) secretes sulfate with significant implications for intestinal sulfate absorption and overall homeostasis. Sulfate is an essential anion that is actively absorbed from the small intestine involving members of the gene family. Here, we show that the main intestinal chloride transporter Slc26a3, known as downregulated in adenoma (DRA), also handles sulfate and contributes to its secretion into the lumen. In the absence of functional DRA (as in the disease congenital chloride diarrhea), net intestinal sulfate absorption was significantly enhanced resulting in substantial alterations to overall sulfate homeostasis.
回肠被认为是无机硫酸盐（[化学式：见正文]）吸收的主要部位。在本研究中，我们探讨了腺瘤下调的顶端氯化物/碳酸氢盐（Cl/[化学式：见正文]）交换体（DRA；Slc26a3）和推定阴离子转运体1（PAT1；Slc26a6）对潜在转运机制的作用。通过测定野生型（WT）、DRA基因敲除（KO）和PAT1基因敲除小鼠离体、短路的回肠远端节段的跨上皮[化学式：见正文]和Cl通量，以及测量尿液和血浆中的硫酸盐来进行研究。WT回肠远端支持硫酸盐的净吸收[197.37±13.61（SE）nmol·cm·h]，但DRA和PAT1均未直接促进单向的黏膜到浆膜通量（[化学式：见正文]），该通量对浆膜（而非黏膜）的DIDS敏感，依赖于Cl，并受cAMP调节。然而，DRA的缺失通过[化学式：见正文]的同时升高和分泌性浆膜到黏膜通量（[化学式：见正文]）降低30%，使硫酸盐净吸收显著增强了三分之一。我们提出，DRA与PAT1一起，通过介导硫酸盐跨顶端膜的外流，对[化学式：见正文]起作用。与体外回肠硫酸盐吸收增加相关，DRA基因敲除小鼠的血浆硫酸盐比WT对照高61%，尿硫酸盐排泄（）高2.2倍，而PAT1基因敲除小鼠的[化学式：见正文]增加了1.8倍。这些硫酸盐稳态的改变不能用肾硫酸盐处理的任何变化来解释，这表明额外硫酸盐的来源是肠道。总之，我们对小鼠回肠远端的跨上皮硫酸盐通量进行了表征，表明DRA（以及在较小程度上的PAT1）分泌硫酸盐，这对肠道硫酸盐吸收和整体稳态具有重要意义。硫酸盐是一种必需阴离子，从小肠中被主动吸收，涉及[基因家族名称未给出]基因家族的成员。在这里，我们表明主要的肠道氯化物转运体Slc26a3，即腺瘤下调的蛋白（DRA），也处理硫酸盐并促进其分泌到肠腔中。在没有功能性DRA的情况下（如在先天性氯化物腹泻疾病中），肠道硫酸盐净吸收显著增强，导致整体硫酸盐稳态发生实质性改变。
