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Liver metabolic/oxidative stress induces hepatic and extrahepatic changes in the expression of the vitamin C transporters SVCT1 and SVCT2

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Abstract

Purpose

Owing to its ability to inactivate harmful radicals, vitamin C plays a key role in antioxidant defense. The bioavailability of this vitamin depends upon the nutritional intake and its uptake by cells, mainly through the sodium-dependent transporters SVCT1/Svct1 and SVCT2/Svct2 (human/rat). Here, we investigated the effect of liver metabolic/oxidative stress on the expression of these transporters in extrahepatic tissues.

Methods and results

In Zucker rats, used here as a model of liver steatosis, Svct1-2 mRNA levels were similar in obese and lean animals, except for lung tissue, where Svct2 was up-regulated. Diabetes mellitus, developed by streptozotocin administration, was accompanied by a down-regulation of Svct1 in liver and kidney, together with a down-regulation of Svct2 in kidney and brain. Complete obstructive cholestasis due to bile duct ligation for 1 week induced a significant down-regulation of both Svct1 and Svct2 in ileum, whereas Svct2 was up-regulated in liver, and no significant changes in the expression of either transporter were found in kidney, brain or lung. In rat hepatoma Can-10 cells, bile acids, but not the FXR agonist GW4064, induced an up-regulation of Svct1 and Svct2. In human hepatoma Alexander cells transfected with FXR/RXRα/OATP1B1, neither GW4064 nor unconjugated or glycine-/taurine-conjugated major bile acids were able to up-regulate either SVCT1 or SVCT2.

Conclusions

Pathological circumstances characterized by the presence of metabolic/oxidative stress in the liver induce different responses in the expression of ascorbic acid transporters in intrahepatic and extrahepatic tissues, which may affect the overall bioavailability and cellular uptake of this vitamin.

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Acknowledgments

The authors thank L. Muñoz, J.F. Martin and J. Villoria for care of the animals. Secretarial help by M.I. Hernandez, technical help by N. Gonzalez and revision of the English spelling, grammar and style of the manuscript by N. Skinner are also gratefully acknowledged. This study was supported in part by the Instituto de Salud Carlos III, FIS (Grant PI11/00337); the Junta de Castilla y Leon (Grants SA021B06, SAN673SA07/08, SA023A11-2, SA070A11-2 and BIO/03/SA23/11), Spain; Ministerio de Ciencia y Tecnologia, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (Grant SAF2010-15517), Spain, and the Fundacion Investigacion Medica Mutua Madrileña (Convocatoria 2009), Spain. The group is member of the Network for Cooperative Research on Membrane Transport Proteins (REIT), and the CIBERehd (Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas) Instituto de Salud Carlos III, Spain. Elisa Lozano and Ester Gonzalez-Sanchez were supported by PhD grants from Junta de Castilla y Leon/Fondo Social Europeo and Ministerio de Educacion AP2008-0376, respectively.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), Department of Physiology and Pharmacology, University of Salamanca, IBSAL, Campus Miguel de Unamuno E.I.D. B-17, 37007, Salamanca, Spain

    Carlos Hierro, Maria J. Monte, Elisa Lozano, Ester Gonzalez-Sanchez, Jose J. G. Marin & Rocio I. R. Macias

  2. National Institute for the Study of Liver and Gastrointestinal Diseases, CIBERehd, Salamanca, Spain

    Maria J. Monte, Jose J. G. Marin & Rocio I. R. Macias

Authors
  1. Carlos Hierro
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  2. Maria J. Monte
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  3. Elisa Lozano
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  4. Ester Gonzalez-Sanchez
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  5. Jose J. G. Marin
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  6. Rocio I. R. Macias
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Correspondence to Rocio I. R. Macias.

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394_2013_536_MOESM5_ESM.tif

Liver histology in controls (A), one-week bile duct ligation (BDL) (B, C), streptozotocin-induced diabetes (D), and 12-week-old lean (E) and obese Zucker rats (F). Original magnification: 10x. Hepatocellular degeneration and neutrophil infiltration, asterisks; ductular proliferation, arrow heads; micro- and macrovesicular steatosis; arrows (TIFF 10785 kb)

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Hierro, C., Monte, M.J., Lozano, E. et al. Liver metabolic/oxidative stress induces hepatic and extrahepatic changes in the expression of the vitamin C transporters SVCT1 and SVCT2. Eur J Nutr 53, 401–412 (2014). https://doi.org/10.1007/s00394-013-0536-4

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