Molecular Pathogenesis of Liver Steatosis Induced by Hepatitis C Virus

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Abstract

Liver steatosis is a pathological hallmark in patients with chronic hepatitis C (CHC). Increased lipid uptake, decreased lipid secretion, increased lipid synthesis and decreased lipid degradation are all involved in pathogenesis of steatosis induced by hepatitic C virus (HCV) infection. Level of low density lipoprotein receptor (LDL-R) and activity of peroxisome proliferator-activated receptor (PPAR) α is related to liver uptake of lipid from circulation, and affected by HCV. Secretion via microsomal triglyceride transfer protein (MTTP), and formation of very low density lipoprotein (VLDL) have been hampered by HCV infection. Up-regulation of lipid synthesis related genes, such as sterol regulatory element-binding protein (SREBP)-1, SREBP-2, SREBP-1c, fatty acid synthase (FASN), HMG CoA reductase (HMGCR), liver X receptor (LXR), acetyl-CoA carboxylase 1 (ACC1), hepatic CB (1) receptors, retinoid X receptor (RXR) α, were the main stay of liver steatosis pathogenesis. Degradation of lipid in liver is decreased in patients with CHC. There is strong evidence that heterogeneity of HCV core genes of different genotypes affect their effects of liver steatosis induction. A mechanism in which steatosis is involved in HCV life cycle is emerging.

1. Chang ML, Yeh HC, Tsou YK, Wang CJ, Cheng HY, Sung CM, et al. HCV core-induced nonobese hepatic steatosis is associated with hypoadiponectinemia and is ameliorated by adiponectin administration. Obesity (Silver Spring) 2012; doi:

2. Sato S, Fukasawa M, Yamakawa Y, Natsume T, Suzuki T, Shoji I, et al. Proteomic profiling of lipid droplet proteins in hepatoma cell lines expressing hepatitis C virus core protein. J Biochem 2006;139:921-930.

3. Congiu M, Ryan MC, Desmond PV. No increase in the expression of key unfolded protein response genes in HCV genotype 3 patients with severe steatosis. Virus Res 2011;160:420-423.

4. Congiu M, Slavin JL, Desmond PV. Expression of common housekeeping genes is affected by disease in human hepatitis C virus-infected liver. Liver Int 2011;31:386-390.

5. Khan M, Jahan S, Khaliq S, Ijaz B, Ahmad W, Samreen B, et al. Interaction of the hepatitis C virus (HCV) core with cellular genes in the development of HCV-induced steatosis. Arch Virol 2010;155:1735-1753.

6. Depla M, d’Alteroche L, Le Gouge A, Moreau A, Hourioux C, Meunier JC, et al. Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis. PLoS One 2012;7(3):e33749.

7. Ivanov AV, Smirnova OA, Ivanova ON, Masalova OV, Kochetkov SN, Isaguliants MG. Hepatitis C virus proteins activate NRF2/ ARE pathway by distinct ROS-dependent and independent mechanisms in HUH7 cells. PLoS One 2011;6:e24957.

8. Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzalez FJ, Aoyama T. PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest 2008;118:683-694.

9. Verdi H, Koytak ES, Onder O, Ergül AA, Cinar K, Idilman R, et al. Peroxisome proliferator-activated receptor alpha L162V polymorphism in nonalcoholic steatohepatitis and genotype 1 hepatitis C virus-related liver steatosis. J Investig Med 2005;53:353-359.

10. Clark P, Thompson A, Vock D, Kratz L, Tolun A, Muir A, et al. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype specific manner. Hepatology 2012; doi:

11. Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chrétien Y, et al. 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 2002;16:185-194.

12. Mirandola S, Osterreicher CH, Marcolongo M, Datz C, Aigner E, Schlabrakowski A, et al. Microsomal triglyceride transfer protein polymorphism (-493G/T) is associated with hepatic steatosis in patients with chronic hepatitis C. Liver Int 2009;29:557-565.

13. Ryan MC, Desmond PV, Slavin JL, Congiu M. Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver. J Viral Hepat 2011;18:53-60.

14. Mirandola S, Realdon S, Iqbal J, Gerotto M, Dal Pero F, Bortoletto G, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology 2006;130:1661-1669.

15. Zampino R, Ingrosso D, Durante-Mangoni E, Capasso R, Tripodi MF, Restivo L, et al. Microsomal triglyceride transfer protein (MTP) -493G/T gene polymorphism contributes to fat liver accumulation in HCV genotype 3 infected patients. J Viral Hepat 2008;15:740-746.

16. Petit JM, Masson D, Minello A, Duvillard L, Galland F, Verges B, et al. Lack of association between microsomal triglyceride transfer protein gene polymorphism and liver steatosis in HCVinfected patients. Mol Genet Metab 2006;88:196-198.

17. Kim K, Kim KH, Kim HY, Cho HK, Sakamoto N, Cheong J. Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway. FEBS Lett 2010;584:707-712.

18. Jackel-Cram C, Qiao L, Xiang Z, Brownlie R, Zhou Y, Babiuk L, et al. Hepatitis C virus genotype-3a core protein enhances sterol regulatory element-binding protein-1 activity through the phosphoinositide 3-kinase-Akt-2 pathway. J Gen Virol 2010;91:1388-1395.

19. Park CY, Jun HJ, Wakita T, Cheong JH, Hwang SB. Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway. J Biol Chem 2009;284:9237-9246.

20. Xiang Z, Qiao L, Zhou Y, Babiuk LA, Liu Q. Hepatitis C virus nonstructural protein-5A activates sterol regulatory elementbinding protein-1c through transcription factor Sp1. Biochem Biophys Res Commun 2010;402:549-553.

21. McPherson S, Jonsson JR, Barrie HD, O’Rourke P, Clouston AD, Powell EE. Investigation of the role of SREBP-1c in the pathogenesis of HCV-related steatosis. J Hepatol 2008;49:1046-1054.

22. Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol 2007;81:8122-8130.

23. Jackel-Cram C, Babiuk LA, Liu Q. Up-regulation of fatty acid synthase promoter by hepatitis C virus core protein: genotype-3a core has a stronger effect than genotype-1b core. J Hepatol 2007;46:999-1008.

24. Oem JK, Jackel-Cram C, Li YP, Zhou Y, Zhong J, Shimano H, et al. Activation of sterol regulatory element-binding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein 2. J Gen Virol 2008;89:1225-1230.

25. Honda A, Matsuzaki Y. Cholesterol and chronic hepatitis C virus infection. Hepatol Res 2011;41:697-710.

26. Kim K, Kim KH, Ha E, Park JY, Sakamoto N, Cheong J. Hepatitis C virus NS5A protein increases hepatic lipid accumulation via induction of activation and expression of PPARgamma. FEBS Lett 2009;583:2720-2726.

27. Lima-Cabello E, García-Mediavilla MV, Miquilena-Colina ME, Vargas-Castrillón J, Lozano-Rodríguez T, Fernández-Bermejo M, et al. Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. Clin Sci (Lond) 2011;120:239-250.

28. Moriishi K, Mochizuki R, Moriya K, Miyamoto H, Mori Y, Abe T, et al. Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci USA 2007;104:1661-1666.

29. Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, et al. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology 2002;35:937-946.

30. Mori Y, Moriishi K, Matsuura Y. Hepatitis C virus core protein: its coordinate roles with PA28gamma in metabolic abnormality and carcinogenicity in the liver. Int J Biochem Cell Biol 2008;40:1437-1442.

31. Fukasawa M, Tanaka Y, Sato S, Ono Y, Nitahara-Kasahara Y, Suzuki T, et al. Enhancement of de novo fatty acid biosynthesis in hepatic cell line Huh7 expressing hepatitis C virus core protein. Biol Pharm Bull 2006;29:1958-1961.

32. van der Poorten D, Shahidi M, Tay E, Sesha J, Tran K, McLeod D, et al. Hepatitis C virus induces the cannabinoid receptor 1. PLoS One 2010;5. pii: e12841.

33. Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S, Fujie H, Shintani Y, et al. Pathogenesis of lipid metabolism disorder in hepatitis C: polyunsaturated fatty acids counteract lipid alterations induced by the core protein. J Hepatol 2011;54:432-438.

34. Mancone C, Montaldo C, Santangelo L, Di Giacomo C, Costa V, Amicone L, et al. Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection. J Proteome Res 2012;11:2786-2797.

35. Tachi Y, Katano Y, Honda T, Hayashi K, Ishigami M, Itoh A, et al. Impact of amino acid substitutions in the hepatitis C virus genotype 1b core region on liver steatosis and hepatic oxidative stress in patients with chronic hepatitis C. Liver Int 2010;30:554-559.

36. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, et al. Amino acid substitutions in the hepatitis C virus core region of genotype 1b are the important predictor of severe insulin resistance in patients without cirrhosis and diabetes mellitus. J Med Virol 2009;81:1032-1039.

37. Sumida Y, Kanemasa K, Hara T, Inada Y, Sakai K, Imai S, et al. Impact of amino acid substitutions in hepatitis C virus genotype 1b core region on liver steatosis and glucose tolerance in noncirrhotic patients without overt diabetes. J Gastroenterol Hepatol 2011;26:836-842.

38. Depla M, Uzbekov R, Hourioux C, Blanchard E, Le Gouge A, Gillet L, et al. Ultrastructural and quantitative analysis of the lipid droplet clustering induced by hepatitis C virus core protein. Cell Mol Life Sci 2010;67:3151-3161.

39. Jhaveri R, McHutchison J, Patel K, Qiang G, Diehl AM. Specific polymorphisms in hepatitis C virus genotype 3 core protein associated with intracellular lipid accumulation. J Infect Dis 2008;197:283-291.

40. Hourioux C, Patient R, Morin A, Blanchard E, Moreau A, Trassard S, et al. The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut 2007;56:1302-1308.

41. Cai T, Dufour JF, Muellhaupt B, Gerlach T, Heim M, Moradpour D, et al. Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis. J Hepatol 2011;55:529-535.

42. Ohnishi M, Tsuge M, Kohno T, Zhang Y, Abe H, Hyogo H, et al. IL28B polymorphism is associated with fatty change in the liver of chronic hepatitis C patients. J Gastroenterol 2012;Feb 18. [Epub ahead of print]PMID: 22350701.

43. Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, et al. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 2010;139:120-129.

44. Clément S, Peyrou M, Sanchez-Pareja A, Bourgoin L, Ramadori P, Suter D, et al. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets. Hepatology 2011;54:38-49.

45. Wedemeyer I, Bechmann LP, Odenthal M, Jochum C, Marquitan G, Drebber U, et al. Adiponectin inhibits steatotic CD95/Fas upregulation by hepatocytes: therapeutic implications for hepatitis C. J Hepatol 2009;50:140-149.

46. Piodi A, Chouteau P, Lerat H, Hézode C, Pawlotsky JM. Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Hepatology 2008;48:16-27.

47. Bernsmeier C, Duong FH, Christen V, Pugnale P, Negro F, Terracciano L, et al. Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C. J Hepatol 2008;49:429-440.

48. Kim KH, Shin HJ, Kim K, Choi HM, Rhee SH, Moon HB, et al. Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma. Gastroenterology 2007;132:1955-1967.

49. Mankouri J, Tedbury PR, Gretton S, Hughes ME, Griffin SD, Dallas ML, et al. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci USA 2010;107:11549-11554.

50. Yang W, Hood BL, Chadwick SL, Liu S, Watkins SC, Luo G, et al. Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production. Hepatology 2008;48:1396-1403.

51. Durante-Mangoni E, Zampino R, Marrone A, Tripodi MF, Rinaldi L, Restivo L, et al. Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumour necrosis factor-alpha in chronic hepatitis C patients. Aliment Pharmacol Ther 2006;24:1349-1357.

52. 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 2002;292:198-210.

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