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High-fat diet consumption reduces hepatic folate transporter expression via nuclear respiratory factor-1

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Abstract

Folate is an essential micronutrient for biological function. The liver, a primary organ for folate metabolism and storage, plays an important role in folate homeostasis. Proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC) are the major folate transporters responsible for folate uptake at basolateral membrane of hepatocytes. Low serum folate levels are frequently associated with obesity. We investigated the mechanism that regulated folate status in a mouse model with diet-induced obesity. Mice (C57BL/6J) were fed a high-fat diet (60% kcal fat) for 8 weeks. Mice displayed increased hepatic lipid accumulation and decreased folate levels in the liver and serum compared to mice fed a normal chow diet (10% kcal fat). High-fat diet-fed mice had low expression of PCFT and RFC and decreased nuclear respiratory factor-1 (NRF-1)/DNA-binding activity. Treatment with NRF-1 siRNA or palmitic acid reduced folate transporter expression in hepatocytes. Inhibition of NRF-1 mediated folate transporter expression significantly reduced intracellular folate levels. These results suggest that chronic consumption of high-fat diets impairs folate transporter expression via NRF-1-dependent mechanism, leading to reduced hepatic folate storage. Understanding the regulation of folate homeostasis in obesity may have an important implication in current guideline of folate intake.

Key messages

  • Serum and liver folate levels are decreased in diet-induced obese mice.

  • Chronic high-fat diet consumption impairs expression of hepatic PCFT and RFC.

  • NRF-1 regulates hepatic folate transporters expression and folate levels.

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Funding

This study was supported, in part, by the Natural Sciences and Engineering Research Council of Canada and St. Boniface Hospital Research Centre.

Author information

Authors and Affiliations

  1. St. Boniface Hospital Research Centre, Winnipeg, Canada

    Victoria Sid, Yaw L. Siow, Yue Shang & Karmin O

  2. Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada

    Victoria Sid, Yaw L. Siow & Karmin O

  3. Agriculture and Agri-Food Canada, Winnipeg, Canada

    Yaw L. Siow

  4. Department of Animal Science, University of Manitoba, Winnipeg, Canada

    Yue Shang & Karmin O

  5. Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, SAR, China

    Connie W. Woo

  6. Laboratory of Integrative Biology, CCARM, St. Boniface Hospital Research Centre, 351 Tache Avenue, Winnipeg, Manitoba, R2H 2A6, Canada

    Karmin O

Authors
  1. Victoria Sid
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  2. Yaw L. Siow
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  3. Yue Shang
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  4. Connie W. Woo
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  5. Karmin O
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Corresponding authors

Correspondence to Connie W. Woo or Karmin O.

Ethics declarations

All procedures were performed in accordance with the Guide to the Care and Use of Experimental Animals published by the Canadian Council on Animal Care and approved by the University of Manitoba Protocol Management and Review Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

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Sid, V., Siow, Y.L., Shang, Y. et al. High-fat diet consumption reduces hepatic folate transporter expression via nuclear respiratory factor-1. J Mol Med 96, 1203–1213 (2018). https://doi.org/10.1007/s00109-018-1688-8

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  • DOI: https://doi.org/10.1007/s00109-018-1688-8

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