Journal of Molecular Medicine

, Volume 96, Issue 11, pp 1203–1213 | Cite as

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

  • Victoria Sid
  • Yaw L. Siow
  • Yue Shang
  • Connie W. WooEmail author
  • Karmin OEmail author
Original Article


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.


Folate High-fat diet Proton-coupled folate transporter Reduced folate carrier Nuclear respiratory factor-1 


Funding information

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

Compliance with ethical standards

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.

Supplementary material

109_2018_1688_MOESM1_ESM.pdf (208 kb)
ESM 1 (PDF 208 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.St. Boniface Hospital Research CentreWinnipegCanada
  2. 2.Department of Physiology and PathophysiologyUniversity of ManitobaWinnipegCanada
  3. 3.Agriculture and Agri-Food CanadaWinnipegCanada
  4. 4.Department of Animal ScienceUniversity of ManitobaWinnipegCanada
  5. 5.Department of Pharmacology and PharmacyThe University of Hong KongHong KongChina
  6. 6.Laboratory of Integrative Biology, CCARMSt. Boniface Hospital Research CentreWinnipegCanada

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