Lipids

, Volume 47, Issue 11, pp 1053–1062 | Cite as

High Serum Palmitic Acid is Associated with Low Antiviral Effects of Interferon-Based Therapy for Hepatitis C Virus

  • Teruki Miyake
  • Yoichi Hiasa
  • Masashi Hirooka
  • Yoshio Tokumoto
  • Takao Watanabe
  • Shinya Furukawa
  • Teruhisa Ueda
  • Shin Yamamoto
  • Teru Kumagi
  • Hiroaki Miyaoka
  • Masanori Abe
  • Bunzo Matsuura
  • Morikazu Onji
Original Article

Abstract

Hepatitis C virus (HCV) infection alters fatty acid synthesis and metabolism in association with HCV replication. The present study examined the effect of serum fatty acid composition on interferon (IFN)-based therapy. Fifty-five patients with HCV were enrolled and received IFN-based therapy. Patient characteristics, laboratory data (including fatty acids), and viral factors that could be associated with the anti-HCV effects of IFN-based therapy were evaluated. The effects of individual fatty acids on viral replication and IFN-based therapy were also examined in an in-vitro system. Multivariate logistic regression analysis showed that the level of serum palmitic acid before treatment and HCV genotype were significant predictors for rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR). High levels of palmitic acid inhibited the anti-HCV effects of IFN-based therapy. HCV replication assays confirmed the inhibitory effects of palmitic acid on anti-HCV therapy. The concentration of serum palmitic acid is an independent predictive factor for RVR, EVR, and SVR in IFN-based antiviral therapy. These results suggest that the effect of IFN-based antiviral therapy in patients with HCV infection might be enhanced by treatment that modulates palmitic acid levels.

Keywords

Fatty acid Hepatitis C virus Interferon Palmitic acid Virological response 

Abbreviations

AUC

Area under curve

BMI

Body mass index

DMEM

Dulbecco’s modified Eagle’s medium

EVR

Early virological response

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

HCC

Hepatocellular carcinoma

HBc

Hepatitis B core

HBs-Ag

Hepatitis B surface antigen

HBV

Hepatitis B virus

HCV

Hepatitis C virus

IFN

Interferon

IL-28B

Interleukin-28B

ISDR

Interferon sensitivity-determining region

NPV

Negative predictive value

NS5

Nonstructural-5

PEG-IFN

Pegylated interferon

PPV

Positive predictive value

RBV

Ribavirin

ROC

Receiver operating characteristics

RVR

Rapid virological response

SVR

Sustained virological response

PCR

Polymerase chain reaction

Supplementary material

11745_2012_3716_MOESM1_ESM.doc (186 kb)
Supplementary material 1 (DOC 185 kb)
11745_2012_3716_MOESM2_ESM.pdf (291 kb)
Supplementary material 2 (PDF 290 kb)
11745_2012_3716_MOESM3_ESM.pdf (351 kb)
Supplementary material 3 (PDF 351 kb)

References

  1. 1.
    Lavanchy D (2009) The global burden of hepatitis C. Liver Int 29:74–81PubMedCrossRefGoogle Scholar
  2. 2.
    Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK (2001) Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 358:958–965PubMedCrossRefGoogle Scholar
  3. 3.
    Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J (2003) Early virologic response to treatment with peginterferon alpha-2a plus ribavirin in patients with chronic hepatitis C. Hepatology 38:645–652PubMedCrossRefGoogle Scholar
  4. 4.
    Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, Schweigler LM, Theodore D, Zacks SL, Liang TJ, Fried MW (2007) Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 46:1548–1563PubMedCrossRefGoogle Scholar
  5. 5.
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867PubMedCrossRefGoogle Scholar
  6. 6.
    Anderson SG, Sanders TA, Cruickshank JK (2009) Plasma fatty acid composition as a predictor of arterial stiffness and mortality. Hypertension 53:839–845PubMedCrossRefGoogle Scholar
  7. 7.
    Miyake T, Akbar SM, Yoshida O, Chen S, Hiasa Y, Matsuura B, Abe M, Onji M (2010) Impaired dendritic cell functions disrupt antigen-specific adaptive immune responses in mice with nonalcoholic fatty liver disease. J Gastroenterol 45:859–867PubMedCrossRefGoogle Scholar
  8. 8.
    Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, Contos MJ, Sterling RK, Fuchs M, Zhou H, Watkins SM, Sanyal AJ (2009) The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 50:1827–1838PubMedCrossRefGoogle Scholar
  9. 9.
    Moriya K, Todoroki T, Tsutsumi T, Fujie H, Shintani Y, Miyoshi H, Ishibashi K, Takayama T, Makuuchi M, Watanabe K, Miyamura T, Kimura S, Koike K (2001) Increase in the concentration of carbon 18 monosaturated fatty acids in the liver with hepatitis C: analysis in transgenic mice and humans. Biochem Biophys Res Commun 281:1207–1212PubMedCrossRefGoogle Scholar
  10. 10.
    Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S, Fujie H, Shintani Y, Fujinaga H, Goto K, Todoroki T, Suzuki T, Miyamura T, Matsuura Y, Yotsuyanagi H, Koike K (2011) Pathogenesis of lipid metabolism disorder in hepatitis C: polyunsaturated fatty acids counteract lipid alterations induced by the core protein. J Hepatol 54:432–438PubMedCrossRefGoogle Scholar
  11. 11.
    Akuta N, Kumada H (2008) Treatment guideline for HCV infection. Nihon Shokakibyo Gakkai Zasshi (in Japanese) 105:186–190Google Scholar
  12. 12.
    Examination Committee of Criteria for ‘Obesity Disease’ in Japan, Japan Society for the Study of Obesity (2002) New criteria for ‘obesity disease’ in Japan. Circ J 66:987–992Google Scholar
  13. 13.
    Chayama K, Tsubota A, Arase Y, Saitoh S, Koida I, Ikeda K, Matsumoto T, Kobayashi M, Iwasaki S, Koyama S, Morinaga T, Kumada H (1993) Genotypic subtyping of hepatitis C virus. J Gastroenterol Hepatol 8:150–156PubMedCrossRefGoogle Scholar
  14. 14.
    Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M (2009) Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 41:1105–1109PubMedCrossRefGoogle Scholar
  15. 15.
    Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461:399–401PubMedCrossRefGoogle Scholar
  16. 16.
    Okamoto K, Akuta N, Kumada H, Kobayashi M, Matsuo Y, Tazawa H (2007) A nucleotide sequence variation detection system for the core region of hepatitis C virus-1b. J Virol Methods 141:1–6PubMedCrossRefGoogle Scholar
  17. 17.
    Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C (1996) Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 334:77–81PubMedCrossRefGoogle Scholar
  18. 18.
    Hiasa Y, Kuzuhara H, Tokumoto Y, Konishi I, Yamashita N, Matsuura B, Michitaka K, Chung RT, Onji M (2008) Hepatitis C virus replication is inhibited by 22beta-methoxyolean-12-ene-3beta, 24(4beta)-diol (ME3738) through enhancing interferon-beta. Hepatology 48:59–69PubMedCrossRefGoogle Scholar
  19. 19.
    Hiasa Y, Blackard JT, Lin W, Kamegaya Y, Horiike N, Onji M, Schmidt EV, Chung RT (2006) Cell-based models of sustained, interferon-sensitive hepatitis C virus genotype 1 replication. J Virol Methods 132:195–203PubMedCrossRefGoogle Scholar
  20. 20.
    Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, Murthy K, Habermann A, Kräusslich HG, Mizokami M, Bartenschlager R, Liang TJ (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11:791–796PubMedCrossRefGoogle Scholar
  21. 21.
    Kapadia SB, Chisari FV (2005) Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA 102:2561–2566PubMedCrossRefGoogle Scholar
  22. 22.
    Leu GZ, Lin TY, Hsu JT (2004) Anti-HCV activities of selective polyunsaturated fatty acids. Biochem Biophys Res Commun 318:275–280PubMedCrossRefGoogle Scholar
  23. 23.
    Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J (1998) Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 352:1426–1432PubMedCrossRefGoogle Scholar
  24. 24.
    Barnes E, Webster G, Whalley S, Dusheiko G (1999) Predictors of a favorable response to alpha interferon therapy for hepatitis C. Clin Liver Dis 3:775–791PubMedCrossRefGoogle Scholar
  25. 25.
    Bressler BL, Guindi M, Tomlinson G, Heathcote J (2003) High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 38:639–644PubMedCrossRefGoogle Scholar
  26. 26.
    Arase Y, Kumada H, Chayama K, Tsubota A, Koida I, Ikeda K, Saitoh S, Matsumoto T, Kobayashi M (1994) Interferon retreatment of nonresponders with HCV-RNA-positive chronic hepatitis C. J Gastroenterol 29:299–304PubMedCrossRefGoogle Scholar
  27. 27.
    Irmisch G, Hoeppner J, Thome J, Richter J, Fernow A, Reisinger EC, Lafrenz M, Loebermann M (2011) Serum fatty acids, antioxidants, and treatment response in hepatitis C infection: greater polyunsaturated fatty acid and antioxidant levels in hepatitis C responders. J Clin Lipidol 5:288–293PubMedCrossRefGoogle Scholar
  28. 28.
    Huang H, Chen Y, Ye J (2007) Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E. Proc Natl Acad Sci USA 104:18666–18670PubMedCrossRefGoogle Scholar
  29. 29.
    Salem ML, El-Demellawy M, El-Azm AR (2010) The potential use of toll-like receptor agonists to restore the dysfunctional immunity induced by hepatitis C virus. Cell Immunol 262:96–104PubMedCrossRefGoogle Scholar
  30. 30.
    Hiasa Y, Horiike N, Akbar SM, Saito I, Miyamura T, Matsuura Y, Onji M (1998) Low stimulatory capacity of lymphoid dendritic cells expressing hepatitis C virus genes. Biochem Biophys Res Commun 249:90–95PubMedCrossRefGoogle Scholar
  31. 31.
    Hiasa Y, Takahashi H, Shimizu M, Nuriya H, Tsukiyama-Kohara K, Tanaka T, Horiike N, Onji M, Kohara M (2004) Major histocompatibility complex class-I presentation impaired in transgenic mice expressing hepatitis C virus structural proteins during dendritic cell maturation. J Med Virol 74:253–261PubMedCrossRefGoogle Scholar
  32. 32.
    Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C (1995) Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. J Clin Invest 96:224–230PubMedCrossRefGoogle Scholar
  33. 33.
    Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H (2007) Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol 46:403–410PubMedCrossRefGoogle Scholar
  34. 34.
    Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Kobayashi M, Arase Y, Ikeda K, Kumada H (2006) Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load. J Med Virol 78:83–90PubMedCrossRefGoogle Scholar

Copyright information

© AOCS 2012

Authors and Affiliations

  • Teruki Miyake
    • 1
  • Yoichi Hiasa
    • 1
  • Masashi Hirooka
    • 1
  • Yoshio Tokumoto
    • 1
  • Takao Watanabe
    • 1
  • Shinya Furukawa
    • 1
  • Teruhisa Ueda
    • 1
  • Shin Yamamoto
    • 1
  • Teru Kumagi
    • 1
  • Hiroaki Miyaoka
    • 2
  • Masanori Abe
    • 1
  • Bunzo Matsuura
    • 1
  • Morikazu Onji
    • 1
  1. 1.Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonJapan
  2. 2.Internal MedicineSaiseikai Matsuyama HospitalMatsuyamaJapan

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