Abstract
We studied the roles of hepatitis C virus (HCV) core protein in hepatic steatosis and changes in hepatic lipid metabolism. HCV core protein expression plasmid was transfected in HepG2 . Triacylglyceride (TG) and mRNA level associated with lipid metabolism were measured. Male C57BL/6 mice were infected with HCV core recombinant adenovirus and used for lipids and mRNA studies. In HCV core protein-expressing cells, peroxisome proliferator-activated receptor (PPAR)α, multidrug resistance protein (MDR) 3, and microsomal triglyceride transfer protein (MTP) were down-regulated 48 hr after transfection. In HCV core protein-expressing mice, hepatic TG content and hepatic thiobarbituric acid-reactive substances increased. PPARα, MDR2, acyl-CoA oxidase (AOX), and carnitine palmitoyl transferase-1 (CPT-1) were down-regulated. HCV core protein down-regulated lipid metabolism-associated gene expression, Mdr2, CPT, and AOX, accompanied by down-regulation of PPARα. There findings may contribute to the understanding of HCV-related steatosis, induction of reactive oxygen species, and carcinogenesis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber MA, Sampliner RE, Meeks EL, Beach MJ: The natural history of community-acquired hepatitis C in the United States. N Engl J Med 327:1899–1905, 1992
Seeff LB, Buskell–Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, Gitnick G, Knodell RG, Perrillo RP, Steevens CE, Hollingworth CG, NHLBI study Group: Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med 327:1906–1911, 1992
Seeff LB: Natural history of hepatitis C. Hepatology 26:21S–28S, 1997
Koziel MJ, Dudley D, Wong JT, Dienstag J, Houghton M, Ralston R, Walker BD: Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol 149:3339–3344, 1992
Cerny A, Chisari FV: Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 30:595–601, 1999
Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Male PJ, Mentha G, Spahr L, Zarski JP, Borisch B, Hadengue A, Negro F: Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 33:106–115, 2000
Scheuer PJ, Davies SE, Dhillon AP: Histopathological aspects of viral hepatitis. J Viral Hepat 3:277–283, 1996
Fujie H, Yotsuyanagi H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, Makuuchi M, Matsuura Y, Miyamura T, Kimura S, Koike K: Steatosis and intrahepatic hepatitis C virus in chronic hepatitis. J Med Virol 59:141–145, 1999
Goodman ZD, Ishak KG: Histopathologic findings in chronic hepatitis C virus infection. Semin Liver Dis 15:70–81, 1995
Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, Eder G, Schaff Z, Chapman MJ, Miyamura T, Brechot C: Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA 94:1200–1205, 1997
Ray RB, Lagging LM, Meyer K, Ray R: Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol 70:4438–4443, 1996
Ray RB, Meyer K, Ray R: Suppression of apoptotic cell death by hepatitis C virus core protein. Virology 226:176–182, 1996
Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C, Lai MM: Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 72:3691–3697, 1998
Honda M, Kaneko S, Shimazaki T, Matsushita E, Kobayashi K, Ping LH, Zhang HC, Lemon SM: Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells. Hepatology 31:1351–1359, 2000
Sakamuro D, Furukawa T, Takegami T. Sakamuro D, Furukawa T, Takegami T: Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 69:3893–3896, 1995
McLauchlan J, Lemberg MK, Hope G, Martoglio B: Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 21:3980–3988, 2002
Shi ST, Polyak SJ, Tu H, Taylor DR, Gretch DR, Lai MM: Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. Virology 292:198–210, 2002
Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y, Miyamura T, Koike K: Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 78:1527–1531, 1997
Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, Okuda M, Gosert R, Xiao SY, Weinman SA, Lemon SM: Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 122:352–365, 2002
Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA: Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366–375, 2002
Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T, Imai K, Todoroki T, Kimura S, Koike K: Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61:4365–4370, 2001
Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K: The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4:1065–1067, 1998
Sabile A, Perlemuter G, Bono F, Kohara K, Demaugre F, Kohara M, Matsuura Y, Miyamura T, Brechot C, Barba G: Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates. Hepatology 30:1064–1076, 1999
Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, Koike K, Pessayre D, Chapman J, Barba G, Brechot C: Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J 16:185–194, 2002
Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K, Tokuda C, Saito I: Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full–length virus genome. Proc Natl Acad Sci USA 93:1320–1324, 1996
Kanegae Y, Lee G, Sato Y, Tanaka M, Nakai M, Sakaki T, Sugano S, Saito I: Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific Cre recombinase. Nucleic Acids Res 23:3816–3821, 1995
Bligh EG, Dyer WJ: A rapid method of total lipid extraction and purification. Can J Med Sci 37:911–917, 1959
Day CP, James OF: Hepatic steatosis: Innocent bystander or guilty party? Hepatology 27:1463–1466, 1988
Fong DG., Nehra V, Lindor KD, Buchman AL: Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology 32:3–10, 2000
Reddy JK: Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 281:G1333–G1339, 2001 (review)
Fan C, Pan J, Chu R, Lee D, Kluckman KD, Usuda N, Singh I, et al.: Hepatocellular and hepatic peroxisomal alternation in mice with a disrupted peroxisomal fatty acyl–coenzyme A oxidase gene. J Biol Chem 271:24698–24710, 1996
Smit JJ, Schinkel AH: Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absense of phospholipid from bile and to liver desease. Cell 75:451–462, 1993
Kok T, Wolters H, Bloks V, Havinga R, Jansen P, Ataels B, Kuipers F: Induction of hepatic ABC transporter expression is part of the PPARα-mediated fasting response in the mouse. Gastroenterology 124:160–171, 2002
Duplus E, Forest C: Is there a single mechanism for fatty acid regulation of gene transcription? Biochem Pharmacol 64:893–901, 2002 (review)
Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K: The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mouse. Nat Med 4:1065–1067, 1998
Yasui K: The native form and maturation process of hepatitis C virus core protein. J Virol 72:6048–6055, 1998
Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujii H, Matsuura Y, Koike K, Miyamura T: Interaction of hepatitis C virus core protein with retinoid X receptor α modulates its transcriptional activity. Hepatology 35:937–946, 2002
Lemberger T, Saladin R, Vazquez M, Assimacopoulos F, Staels B, Desvergne B, Wahli W, Auwerx J: Expression of the peroxisome proliferators-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem. 19:1764–1769, 1996
Hsu M, Savas U, Griffin K, Johnson E: Identification of peroxisome proliferators-responsive human genes by elevated expression of peroxisome proliferators-activated receptor α in HepG2 Cells. J. Biol. Chem 276:27950–27958, 2001
Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR: Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38:1008–1017, 2003
Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber MA, Sampliner RE, Meeks EL, Beach MJ: The natural history of community-acquired hepatitis C in the United States. N Engl J Med 327:1899–1905,1992
Seeff LB, Buskell–Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, Gitnick G, Knodell RG, Perrillo RP, Steevens CE, Hollingworth CG, NHLBI study Group: Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med 327:1906–1911, 1992
Seeff LB: Natural history of hepatitis C. Hepatology 26:21S–28S, 1997
Koziel MJ, Dudley D, Wong JT, Dienstag J, Houghton M, Ralston R, Walker BD: Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol 149:3339–3344, 1992
Cerny A, Chisari FV: Pathogenesis of chronic hepatitis C: immunological features of hepatic injury and viral persistence. Hepatology 30:595–601, 1999
Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Male PJ, Mentha G, Spahr L, Zarski JP, Borisch B, Hadengue A, Negro F: Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 33:106–115, 2000
Scheuer PJ, Davies SE, Dhillon AP: Histopathological aspects of viral hepatitis. J Viral Hepat 3:277–283, 1996
Fujie H, Yotsuyanagi H, Moriya K, Shintani Y, Tsutsumi T, Takayama T, Makuuchi M, Matsuura Y, Miyamura T, Kimura S, Koike K: Steatosis and intrahepatic hepatitis C virus in chronic hepatitis. J Med Virol 59:141–145, 1999
Goodman ZD, Ishak KG: Histopathologic findings in chronic hepatitis C virus infection. Semin Liver Dis 15:70–81, 1995
Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, Eder G, Schaff Z, Chapman MJ, Miyamura T, Brechot C: Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA 94:1200–1205, 1997
Ray RB, Lagging LM, Meyer K, Ray R: Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol 70:4438–4443, 1996
Ray RB, Meyer K, Ray R: Suppression of apoptotic cell death by hepatitis C virus core protein. Virology 226:176–182, 1996
Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C, Lai MM: Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 72:3691–3697, 1998
Honda M, Kaneko S, Shimazaki T, Matsushita E, Kobayashi K, Ping LH, Zhang HC, Lemon SM: Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells. Hepatology 31:1351–1359, 2000
Sakamuro D, Furukawa T, Takegami T. Sakamuro D, Furukawa T, Takegami T: Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 69:3893–3896, 1995
McLauchlan J, Lemberg MK, Hope G, Martoglio B: Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 21:3980–3988, 2002
Shi ST, Polyak SJ, Tu H, Taylor DR, Gretch DR, Lai MM: Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. Virology 292:198–210, 2002
Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y, Miyamura T, Koike K: Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 78:1527–1531, 1997
Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, Okuda M, Gosert R, Xiao SY, Weinman SA, Lemon SM: Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 122:352–365, 2002
Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA: Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366–375, 2002
Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T, Imai K, Todoroki T, Kimura S, Koike K: Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61:4365–4370, 2001
Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K: The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4:1065–1067, 1998
Sabile A, Perlemuter G, Bono F, Kohara K, Demaugre F, Kohara M, Matsuura Y, Miyamura T, Brechot C, Barba G: Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates. Hepatology 30:1064–1076, 1999
Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, Koike K, Pessayre D, Chapman J, Barba G, Brechot C: Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J 16:185–194, 2002
Miyake S, Makimura M, Kanegae Y, Harada S, Sato Y, Takamori K, Tokuda C, Saito I: Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full–length virus genome. Proc Natl Acad Sci USA 93:1320–1324, 1996
Kanegae Y, Lee G, Sato Y, Tanaka M, Nakai M, Sakaki T, Sugano S, Saito I: Efficient gene activation in mammalian cells by using recombinant adenovirus expressing site-specific Cre recombinase. Nucleic Acids Res 23:3816–3821, 1995
Bligh EG, Dyer WJ: A rapid method of total lipid extraction and purification. Can J Med Sci 37:911–917, 1959
Day CP, James OF: Hepatic steatosis: Innocent bystander or guilty party? Hepatology 27:1463–1466, 1988
Fong DG., Nehra V, Lindor KD, Buchman AL: Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology 32:3–10, 2000
Reddy JK: Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 281:G1333–G1339, 2001 (review)
Fan C, Pan J, Chu R, Lee D, Kluckman KD, Usuda N, Singh I, et al.: Hepatocellular and hepatic peroxisomal alternation in mice with a disrupted peroxisomal fatty acyl–coenzyme A oxidase gene. J Biol Chem 271:24698–24710, 1996
Smit JJ, Schinkel AH: Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absense of phospholipid from bile and to liver desease. Cell 75:451–462, 1993
Kok T, Wolters H, Bloks V, Havinga R, Jansen P, Ataels B, Kuipers F: Induction of hepatic ABC transporter expression is part of the PPARα-mediated fasting response in the mouse. Gastroenterology 124:160–171, 2002
Duplus E, Forest C: Is there a single mechanism for fatty acid regulation of gene transcription? Biochem Pharmacol 64:893–901, 2002 (review)
Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K: The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mouse. Nat Med 4:1065–1067, 1998
Yasui.K: The native form and maturation process of hepatitis C virus core protein. J Virol 72:6048–6055, 1998
Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujii H, Matsuura Y, Koike K, Miyamura T: Interaction of hepatitis C virus core protein with retinoid X receptor α modulates its transcriptional activity. Hepatology 35:937–946, 2002
Lemberger T, Saladin R, Vazquez M, Assimacopoulos F, Staels B, Desvergne B, Wahli W, Auwerx J: Expression of the peroxisome proliferators-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem. 19:1764–1769, 1996
Hsu M, Savas U, Griffin K, Johnson E: Identification of peroxisome proliferators-responsive human genes by elevated expression of peroxisome proliferators-activated receptor α in HepG2 Cells. J. Biol. Chem 276:27950–27958, 2001
Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR: Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38:008–1017, 2003
Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH: A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39:188–196, 2004
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yamaguchi, A., Tazuma, S., Nishioka, T. et al. Hepatitis C Virus Core Protein Modulates Fatty Acid Metabolism and Thereby Causes Lipid Accumulation in the Liver. Dig Dis Sci 50, 1361–1371 (2005). https://doi.org/10.1007/s10620-005-2788-1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10620-005-2788-1