Advertisement

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
  • 265 Downloads

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.

Keywords

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

Notes

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)

References

  1. 1.
    Stover PJ, Field MS (2011) Trafficking of intracellular folates. Adv Nutr 2(4):325–331CrossRefGoogle Scholar
  2. 2.
    Zhao R, Matherly LH, Goldman ID (2009) Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues. Expert Rev Mol Med 11:e4CrossRefGoogle Scholar
  3. 3.
    Centers for Disease C, Prevention (2010) CDC Grand Rounds: additional opportunities to prevent neural tube defects with folic acid fortification. MMWR Morb Mortal Wkly Rep 59(31):980–984Google Scholar
  4. 4.
    Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, Sempos CA, Burt VL, Radimer KL, Picciano MF (2010) Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr 91(1):231–237CrossRefGoogle Scholar
  5. 5.
    Mahabir S, Ettinger S, Johnson L, Baer DJ, Clevidence BA, Hartman TJ, Taylor PR (2008) Measures of adiposity and body fat distribution in relation to serum folate levels in postmenopausal women in a feeding study. Eur J Clin Nutr 62(5):644–650CrossRefGoogle Scholar
  6. 6.
    Mojtabai R (2004) Body mass index and serum folate in childbearing age women. Eur J Epidemiol 19(11):1029–1036CrossRefGoogle Scholar
  7. 7.
    da Silva VR, Hausman DB, Kauwell GP, Sokolow A, Tackett RL, Rathbun SL, Bailey LB (2013) Obesity affects short-term folate pharmacokinetics in women of childbearing age. Int J Obes 37(12):1608–1610CrossRefGoogle Scholar
  8. 8.
    Xia MF, Bian H, Zhu XP, Yan HM, Chang XX, Zhang LS, Lin HD, Hu XQ, Gao X (2017) Serum folic acid levels are associated with the presence and severity of liver steatosis in Chinese adults. Clin Nutr.  https://doi.org/10.1016/j.clnu.2017.06.021 CrossRefGoogle Scholar
  9. 9.
    Klipstein FA, Lindenbaum J (1965) Folate deficiency in chronic liver disease. Blood 25:443–456PubMedGoogle Scholar
  10. 10.
    Leblanc M, Pichette V, Geadah D, Ouimet D (2000) Folic acid and pyridoxal-5′-phosphate losses during high-efficiency hemodialysis in patients without hydrosoluble vitamin supplementation. J Ren Nutr 10(4):196–201CrossRefGoogle Scholar
  11. 11.
    Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, Sandoval C, Zhao R, Akabas MH, Goldman ID (2006) Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127(5):917–928CrossRefGoogle Scholar
  12. 12.
    Loomba R, Sanyal AJ (2013) The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol 10(11):686–690CrossRefGoogle Scholar
  13. 13.
    Sid V, Siow YL, O K (2017) Role of folate in non-alcoholic fatty liver disease (NAFLD). Can J Physiol Pharmacol.  https://doi.org/10.1139/cjpp-2016-0681 CrossRefGoogle Scholar
  14. 14.
    Must A, McKeown NM (2000) The disease burden associated with overweight and obesity. In: De Groot LJ, Chrousos G, Dungan K et al. (eds) Endotext. South Dartmouth (MA): MD Text.com, Inc; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279095/
  15. 15.
    Hirsch S, Poniachick J, Avendano M, Csendes A, Burdiles P, Smok G, Diaz JC, de la Maza MP (2005) Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition 21(2):137–141CrossRefGoogle Scholar
  16. 16.
    Angulo P (2007) Obesity and nonalcoholic fatty liver disease. Nutr Rev 65(6 Pt 2):S57–S63CrossRefGoogle Scholar
  17. 17.
    Golay A, Bobbioni E (1997) The role of dietary fat in obesity. Int J Obes Relat Metab Disord 21(Suppl 3):S2–S11PubMedGoogle Scholar
  18. 18.
    Hebbard L, George J (2011) Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 8(1):35–44CrossRefGoogle Scholar
  19. 19.
    Wu N, Sarna LK, Hwang SY, Zhu Q, Wang P, Siow YL, O K (2013) Activation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase during high fat diet feeding. Biochim Biophys Acta 1832 (10):1560–1568CrossRefGoogle Scholar
  20. 20.
    Sarna LK, Wu N, Wang P, Hwang SY, Siow YL, O K (2012) Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Can J Physiol Pharmacol 90 (2):155–165. doi:Google Scholar
  21. 21.
    Sid V, Wu N, Sarna LK, Siow YL, House JD, O K (2015) Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism. Am J Phys Regul Integr Comp Phys 309 (10):R1215–R1225. doi:Google Scholar
  22. 22.
    Steinberg SE (1984) Mechanisms of folate homeostasis. Am J Phys 246(4 Pt 1):G319–G324Google Scholar
  23. 23.
    Steinberg SE, Campbell CL, Hillman RS (1979) Kinetics of the normal folate enterohepatic cycle. J Clin Invest 64(1):83–88CrossRefGoogle Scholar
  24. 24.
    Wright AJ, Dainty JR, Finglas PM (2007) Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr 98(4):667–675CrossRefGoogle Scholar
  25. 25.
    Zhao R, Diop-Bove N, Visentin M, Goldman ID (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annu Rev Nutr 31:177–201CrossRefGoogle Scholar
  26. 26.
    Medici V, Halsted CH (2013) Folate, alcohol, and liver disease. Mol Nutr Food Res 57(4):596–606CrossRefGoogle Scholar
  27. 27.
    Gonen N, Assaraf YG (2010) The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1. J Biol Chem 285(44):33602–33613CrossRefGoogle Scholar
  28. 28.
    Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226(1):497–509Google Scholar
  29. 29.
    Fraser DA, Thoen J, Rustan AC, Forre O, Kjeldsen-Kragh J (1999) Changes in plasma free fatty acid concentrations in rheumatoid arthritis patients during fasting and their effects upon T-lymphocyte proliferation. Rheumatology (Oxford) 38(10):948–952CrossRefGoogle Scholar
  30. 30.
    Joshi-Barve S, Barve SS, Amancherla K, Gobejishvili L, Hill D, Cave M, Hote P, McClain CJ (2007) Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes. Hepatology 46(3):823–830CrossRefGoogle Scholar
  31. 31.
    Woo CW, Siow YL, Pierce GN, Choy PC, Minuk GY, Mymin D, O K (2005) Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors. Am J Phys Endocrinol Metab 288(5):E1002–E1010CrossRefGoogle Scholar
  32. 32.
    Woo CW, Siow YL, O K (2006) Homocysteine activates cAMP-response element binding protein in HepG2 through cAMP/PKA signaling pathway. Arterioscler Thromb Vasc Biol 26(5):1043–1050CrossRefGoogle Scholar
  33. 33.
    Ahmad Najar R, Rahat B, Hussain A, Thakur S, Kaur J, Kaur J, Hamid A (2016) Gene specific epigenetic regulation of hepatic folate transport system is responsible for perturbed cellular folate status during aging and exogenous modulation. Mol Nutr Food Res 60(6):1501–1513CrossRefGoogle Scholar
  34. 34.
    Liu M, Ge Y, Cabelof DC, Aboukameel A, Heydari AR, Mohammad R, Matherly LH (2005) Structure and regulation of the murine reduced folate carrier gene: identification of four noncoding exons and promoters and regulation by dietary folates. J Biol Chem 280(7):5588–5597CrossRefGoogle Scholar
  35. 35.
    Champier J, Claustrat F, Nazaret N, Fevre Montange M, Claustrat B (2012) Folate depletion changes gene expression of fatty acid metabolism, DNA synthesis, and circadian cycle in male mice. Nutr Res 32(2):124–132CrossRefGoogle Scholar
  36. 36.
    Christensen KE, Wu Q, Wang X, Deng L, Caudill MA, Rozen R (2010) Steatosis in mice is associated with gender, folate intake, and expression of genes of one-carbon metabolism. J Nutr 140(10):1736–1741CrossRefGoogle Scholar
  37. 37.
    Ahmed A, Wong RJ, Harrison SA (2015) Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol 13(12):2062–2070CrossRefGoogle Scholar
  38. 38.
    Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E (2018) Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 15(1):11–20CrossRefGoogle Scholar
  39. 39.
    Updegraff TA, Neufeld NJ (1981) Protein, iron, and folate status of patients prior to and following surgery for morbid obesity. J Am Diet Assoc 78(2):135–140PubMedGoogle Scholar

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

Personalised recommendations