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Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors.

ABSTRACT: Mutations in human equilibrative nucleoside transporter 3 (ENT3) encoded by SLC29A3 results in anemia and erythroid hypoplasia, suggesting that ENT3 may regulate erythropoiesis. Here, we demonstrate that lysosomal ENT3 transport of taurine-conjugated bile acids (TBA) facilitates TBA chemical chaperone function and alleviates endoplasmic reticulum (ER) stress in expanding mouse hematopoietic stem and progenitor cells (HSPCs). Slc29a3^-/- HSPCs accumulate less TBA despite elevated levels of TBA in Slc29a3^-/- mouse plasma and have elevated basal ER stress, reactive oxygen species (ROS), and radiation-induced apoptosis. Reintroduction of ENT3 allows for increased accumulation of TBA into HSPCs, which results in TBA-mediated alleviation of ER stress and erythroid apoptosis. Transplanting TBA-preconditioned HSPCs expressing ENT3 into Slc29a3^-/- mice increase bone marrow repopulation capacity and erythroid pool size and prevent early mortalities. Together, these findings suggest a putative role for a facilitative lysosomal transporter in the bile acid regulation of ER stress in mouse HSPCs which may have implications in erythroid biology, the treatment of anemia observed in ENT3-mutated human genetic disorders, and nucleoside analog drug therapy.

SUBMITTER: Persaud AK

PROVIDER: S-EPMC7902824 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors.

Persaud Avinash K AK Nair Sreenath S Rahman Md Fazlur MF Raj Radhika R Weadick Brenna B Nayak Debasis D McElroy Craig C Shanmugam Muruganandan M Knoblaugh Sue S Cheng Xiaolin X Govindarajan Rajgopal R

Nature communications 20210223 1

Mutations in human equilibrative nucleoside transporter 3 (ENT3) encoded by SLC29A3 results in anemia and erythroid hypoplasia, suggesting that ENT3 may regulate erythropoiesis. Here, we demonstrate that lysosomal ENT3 transport of taurine-conjugated bile acids (TBA) facilitates TBA chemical chaperone function and alleviates endoplasmic reticulum (ER) stress in expanding mouse hematopoietic stem and progenitor cells (HSPCs). Slc29a3<sup>-/-</sup> HSPCs accumulate less TBA despite elevated levels ...[more]

PMID: 33623001

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Project description:Pectin has been known to lower circulating cholesterol by interacting with bile acid (BA) metabolism. The current study was aimed to investigate intestinal BA transport at the molecular level in a pig model. Twelve young pigs (11.05 ± 0.11 kg) were randomly divided into 2 groups and fed corn-soybean meal diets with either 5% pectin or cornstarch for 72 d. In pigs fed with pectin, total cholesterol and low-density lipoprotein cholesterol (LDL-C) were lowered but high-density lipoprotein (HDL-C) was increased (P < 0.05). Serum triglycerides tended to be lower in the pectin-fed animals (P = 0.093), whereas no change was noted in serum total bile acid. Along the length of the intestine, the size and composition of BA pools vary. The ratio of primary, secondary, taurine-conjugated, and glycine-conjugated BAs in the ileal pool was about 46:15:9:30, whereas it was 28:61:1:11 in the cecum and 22:65:3:9 in the colon (P < 0.05). In the feces, lithocholic acid and ursodeoxycholic acid (UDCA) made up of over 97% of the total BA pool. Overall, the ileum had the greatest expression of farnesoid X receptor (FXR) and apical sodium-coupled bile acid transporter (ASBT) than the duodenum, jejunum, cecum, and colon (P < 0.05), whereas organic solute transporters α/β (OSTα/β) gene expression was peaked in the ileum and jejunum (P < 0.05). Expression multidrug resistance protein 2 (MRP2) gradually decreased towards the end of the intestine (P < 0.05). Greater expression of G protein-coupled bile acid receptor and multidrug resistance protein 3 (MRP3) was found in the cecum and colon (P < 0.05). In pigs fed with 5% pectin, only cecal UDCA (P = 0.097) and hyocholic acid (P = 0.088) showed a decreasing tendency. But FXR, ASBT, and MRP2 were upregulated in the ileum and FXR, OSTα/β, MRP2, and MRP3 in the cecum of PEC-fed pigs (P < 0.05). Liver enzymes involved in BA biosynthesis (CYP7A1, CYP27A1, bile acid-CoA synthase, and bile acid-CoA:amino acid N acyltransferase) were not affected by pectin consumption. In conclusion, the abundant distribution of BA transporters and the greater BA pool size suggests the ileum as the major site for intestinal BA reabsorption in pigs. In the ileum, pectin increased in-and-out BA transport on the apical membrane by increasing ASBT and MRP2, but it increased the overall BA transport in the cecum by increasing OSTα/β and MRP3.

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Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors.

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Facilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors.

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