Skip to main content
SpringerLink
Log in

Hepatic n-3/n-6 polyunsaturated fatty acid shift improves hepatic steatosis in farnesoid X receptor-null mice

  • Original Article
  • Chemistry and Biochemistry
  • Published:
Fisheries Science Aims and scope Submit manuscript

Abstract

Mice lacking farnesoid X receptor (Fxr-null mice) are used as a model of non-alcoholic fatty liver disease because they exhibit higher levels of hepatic lipids and hepatic damage-associated diagnostic markers. The influence of hepatic accumulation of n-3 polyunsaturated fatty acid (PUFA) was investigated using Fxr-null mice fed either a corn oil (4 %) or fish oil (4 %) diet for 4 weeks. Hepatic accumulation of n-3 PUFA was observed in the fish-oil group. No significant differences in the activity of hepatic damage-associated diagnostic markers such as serum alanine aminotransferase were observed between the two groups. The levels of hepatic triglyceride, free fatty acid (FFA) and total cholesterol were significantly lower in the fish-oil group than in the corn-oil group. Marked decreases in lipid droplets were observed in the livers of mice in the fish-oil group. Only serum FFA levels were significantly lower in the fish-oil group than in the corn-oil group. Hepatic mRNA and protein levels of lipogenic enzymes, fatty acid synthase, and stearoyl CoA desaturase 1 were significantly lower in the fish-oil group than in the corn-oil group. These results suggest that hepatic n-3/n-6 PUFA shift improves hepatic steatosis by altering hepatic lipogenesis in Fxr-null mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

PUFA:

Polyunsaturated fatty acids

ALT:

Alanine aminotransferase

ALP:

Alkaline phosphatase

EPA:

Eicosapentaenoic acid

DHA:

Docosahexaenoic acid

FFA:

Free fatty acid

TAG:

Triglyceride

TC:

Total cholesterol

qPCR:

Quantitative polymerase chain reaction

References

  1. Rustan AC, Nossen JO, Christiansen EN, Drevon CA (1988) Eicosapentaenoic acid reduces hepatic synthesis and secretion of triacylglycerol by decreasing the activity of acyl-coenzyme A:1,2-diacylglycerol acyltransferase. J Lipid Res 29:1417–1426

    CAS  PubMed  Google Scholar 

  2. Harris WS, Hustvedt BE, Hagen E, Green MH, Lu G, Drevon CA (1997) N-3 fatty acids and chylomicron metabolism in the rat. J Lipid Res 38:503–515

    CAS  PubMed  Google Scholar 

  3. Mori TA, Burke V, Puddey IB, Watts GF, O’Neal DN, Best JD, Beilin LJ (2000) Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. Am J Clin Nutr 71:1085–1094

    CAS  PubMed  Google Scholar 

  4. Nakamura MT, Cheon Y, Li Y, Nara TY (2004) Mechanisms of regulation of gene expression by fatty acids. Lipids 39:1077–1083

    Article  CAS  PubMed  Google Scholar 

  5. Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O (2005) Fatty acid regulation of hepatic gene transcription. J Nutr 135:2503–2506

    CAS  PubMed  Google Scholar 

  6. Worgall TS, Sturley SL, Seo T, Osborne TF, Deckelbaum RJ (1998) Polyunsaturated fatty acids decrease expression of promoters with sterol regulatory elements by decreasing levels of mature sterol regulatory element-binding protein. J Biol Chem 273:25537–25540

    Article  CAS  PubMed  Google Scholar 

  7. Mater MK, Thelen AP, Pan DA, Jump DB (1999) Sterol response element-binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty acid suppression of hepatic S14 gene transcription. J Biol Chem 274:32725–32732

    Article  CAS  PubMed  Google Scholar 

  8. Xu J, Teran-Garcia M, Park JH, Nakamura MT, Clarke SD (2001) Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. J Biol Chem 276:9800–9807

    Article  CAS  PubMed  Google Scholar 

  9. Xu J, Nakamura MT, Cho HP, Clarke SD (1999) Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem 274:23577–23583

    Article  CAS  PubMed  Google Scholar 

  10. Schmitz G, Ecker J (2008) The opposing effects of n-3 and n-6 fatty acids. Prog Lipid Res 47:147–155

    Article  CAS  PubMed  Google Scholar 

  11. Bagga D, Wang L, Farias-Eisner R, Glaspy JA, Reddy ST (2003) Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci USA 100:1751–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Robinson JG, Stone NJ (2006) Antiatherosclerotic and antithrombotic effects of omega-3 fatty acids. Am J Cardiol 98:39i–49i

    Article  CAS  PubMed  Google Scholar 

  13. Lo CJ, Chiu KC, Fu M, Lo R, Helton S (1999) Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res 82:216–221

    Article  CAS  PubMed  Google Scholar 

  14. Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96

    Article  CAS  PubMed  Google Scholar 

  15. Kemper JK (2011) Regulation of FXR transcriptional activity in health and disease: emerging roles of FXR cofactors and post-translational modifications. Biochim Biophys Acta 1812:842–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Novak TE, Babcock TA, Jho DH, Helton WS, Espat NJ (2003) NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Lung Cell Mol Physiol 284:L84–L89

    Article  CAS  PubMed  Google Scholar 

  17. Wang H, Chen J, Hollister K, Sowers LC, Forman BM (1999) Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553

    Article  CAS  PubMed  Google Scholar 

  18. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM (1999) Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368

    Article  CAS  PubMed  Google Scholar 

  19. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365

    Article  CAS  PubMed  Google Scholar 

  20. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–744

    Article  CAS  PubMed  Google Scholar 

  21. Kitada H, Miyata M, Nakamura T, Tozawa A, Honma W, Shimada M, Nagata K, Sinal CJ, Guo GL, Gonzalez FJ, Yamazoe Y (2003) Protective role of hydroxysteroid sulfotransferase in lithocholic acid-induced liver toxicity. J Biol Chem 278:17838–17844

    Article  CAS  PubMed  Google Scholar 

  22. Miyata M, Sakaida Y, Matsuzawa H, Yoshinari K, Yamazoe Y (2011) Fibroblast growth factor 19 treatment ameliorates disruption of hepatic lipid metabolism in farnesoid X receptor (Fxr)-null mice. Biol Pharm Bull 34:1885–1889

    Article  CAS  PubMed  Google Scholar 

  23. Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Investig 118:829–838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y (2006) FXR, a multipurpose nuclear receptor. Trends Biochem Sci 31:572–580

    Article  CAS  PubMed  Google Scholar 

  26. Cariou B, Staels B (2007) FXR: a promising target for the metabolic syndrome? Trends Pharmacol Sci 28:236–243

    Article  CAS  PubMed  Google Scholar 

  27. Wang YD, Chen WD, Moore DD, Huang W (2008) FXR: a metabolic regulator and cell protector. Cell Res 18:1087–1095

    Article  CAS  PubMed  Google Scholar 

  28. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nguyen KA, Carbone JM, Silva VM, Chen C, Hennig GE, Whiteley HE, Manautou JE (1999) The PPAR activator docosahexaenoic acid prevents acetaminophen hepatotoxicity in male CD-1 mice. J Toxicol Environ Health A 58:171–186

    Article  CAS  PubMed  Google Scholar 

  30. Lee S, Kim S, Le HD, Meisel J, Strijbosch RA, Nose V, Puder M (2008) Reduction of hepatocellular injury after common bile duct ligation using omega-3 fatty acids. J Pediatr Surg 43:2010–2015

    Article  PubMed  Google Scholar 

  31. Turkez H, Geyikoglu F, Yousef MI (2012) Ameliorative effect of docosahexaenoic acid on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced histological changes, oxidative stress, and DNA damage in rat liver. Toxicol Ind Health 28:687–696

    Article  CAS  PubMed  Google Scholar 

  32. Jung UJ, Millman PN, Tall AR, Deckelbaum RJ (2011) n-3 fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice. Biochim Biophys Acta 1811:491–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tulubas F, Gurel A, Oran M, Topcu B, Caglar V, Uygur E (2015) The protective effects of omega-3 fatty acids on doxorubicin-induced hepatotoxicity and nephrotoxicity in rats. Toxicol Ind Health 31:638–644

    Article  CAS  PubMed  Google Scholar 

  34. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL (1999) Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA 96:13656–13661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hannah VC, Ou J, Luong A, Goldstein JL, Brown MS (2001) Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells. J Biol Chem 276:4365–4372

    Article  CAS  PubMed  Google Scholar 

  36. Matsukuma KE, Bennett MK, Huang J, Wang L, Gil G, Osborne TF (2006) Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase. J Lipid Res 47:2754–2761

    Article  CAS  PubMed  Google Scholar 

  37. Shen LL, Liu H, Peng J, Gan L, Lu L, Zhang Q, Li L, He F, Jiang Y (2011) Effects of farnesoid X receptor on the expression of the fatty acid synthetase and hepatic lipase. Mol Biol Rep 38:553–559

    Article  CAS  PubMed  Google Scholar 

  38. Duran-Sandoval D, Cariou B, Percevault F, Hennuyer N, Grefhorst A, van Dijk TH, Gonzalez FJ, Fruchart JC, Kuipers F, Staels B (2005) The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem 280:29971–29979

    Article  CAS  PubMed  Google Scholar 

  39. Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Investig 113:1408–1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B (2003) Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17:259–272

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant 21390039) and from the Ministry of Agriculture, Forestry and Fisheries of Japan in 2014.

Author information

Authors and Affiliations

  1. Department of Food Science and Technology, National Fisheries University, 2-7-1 Nagata-honmachi, Shimonoseki, 759-6595, Japan

    Masaaki Miyata, Yuichi Kinoshita, Kouhei Shinno, Yoshimasa Sugiura & Kazuki Harada

Authors
  1. Masaaki Miyata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuichi Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kouhei Shinno
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshimasa Sugiura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuki Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masaaki Miyata.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyata, M., Kinoshita, Y., Shinno, K. et al. Hepatic n-3/n-6 polyunsaturated fatty acid shift improves hepatic steatosis in farnesoid X receptor-null mice. Fish Sci 82, 529–536 (2016). https://doi.org/10.1007/s12562-016-0984-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12562-016-0984-x

Keywords

Search

Navigation