Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

Laboratory Investigation

Volumn 92, Issue 8, 2012, Pages 1191-1202

  García Mediavilla, María Victoria ^a,b   Pisonero Vaquero, Sandra ^a   Lima Cabello, Elena ^a   Benedicto, Ignacio ^b,c   Majano, Pedro Lorenzo ^b,c   Jorquera, Francisco ^b,d   González Gallego, Javier ^a,b   Sánchez Campos, Sonia ^a,b  

^a UNIVERSITY OF LEÓN   (Spain)

^b INSTITUTO DE SALUD CARLOS III   (Spain)

^c HOSPITAL UNIVERSITARIO DE LA PRINCESA   (Spain)

^d Complejo Asistencial de León ^*  (Spain)

Author keywords

HCV proteins; HCV replication; lipogenic genes; LXR; PI3K AKT pathway; steatosis

Indexed keywords

3 [3 [[2 CHLORO 3 (TRIFLUOROMETHYL)BENZYL](2 DIPHENYLETHYL)AMINO]PROPOXY]PHENYLACETIC ACID; CORE PROTEIN; FATTY ACID SYNTHASE; LIVER X RECEPTOR ALPHA; NONSTRUCTURAL PROTEIN 5A; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE; SMALL INTERFERING RNA; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C;

ARTICLE; CONTROLLED STUDY; FATTY LIVER; GENE EXPRESSION; GENE SILENCING; GENETIC TRANSCRIPTION; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; IN VITRO STUDY; LIPID STORAGE; LIPOGENESIS; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROMOTER REGION; RECEPTOR UPREGULATION; REPLICON; VIRUS REPLICATION;

ANALYSIS OF VARIANCE; ANTIGENS, CD95; CELL LINE, TUMOR; FATTY LIVER; FLOW CYTOMETRY; GENE EXPRESSION REGULATION; GENE KNOCKDOWN TECHNIQUES; HEPACIVIRUS; HOST-PATHOGEN INTERACTIONS; HUMANS; LIPOGENESIS; ONCOGENE PROTEIN V-AKT; ORPHAN NUCLEAR RECEPTORS; PHOSPHATIDYLINOSITOL 3-KINASES; PPAR GAMMA; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; VIRAL CORE PROTEINS; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84864475305     PISSN: 00236837     EISSN: 15300307     Source Type: Journal    
DOI: 10.1038/labinvest.2012.88     Document Type: Article

References (53)

1. Reed KE, Rice CM. Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr Top Microbiol Immunol 2000;242:55-84.
2. Huang Y, Staschke K, De Francesco R, et al. Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication? Virology 2007;20:1-9.
3. Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 2000;20:1-16.
4. Lok AS, Everhart JE, Chung RT, et al. Hepatic steatosis in hepatitis C: comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial. Clin Gastroenterol Hepatol 2007;5:245-254.
5. Lonardo A, Loria P, Adinolfi LE, et al. Hepatitis C and steatosis: a reappraisal. J Viral Hepat 2006;13:73-80.
6. Itoh Y, Nishimura T, Yamaguchi K, et al. Hepatic steatosis in chronic hepatitis C patients infected with genotype 2 is associated with insulin resistance, hepatic fibrosis and affects cumulative positivity of serum hepatitis C virus RNA in peginterferon and ribavirin combination therapy. Hepatol Res 2011;41:1145-1152.
7. Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? J Hepatol 2012;56:S56-S65.
8. Negro F, Sanyal AJ. Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data. Liver Int 2009;29:26-37.
9. González-Gallego J, Garća-Mediavilla MV, Sánchez-Campos S. Hepatitis C virus oxidative stress and steatosis: current status and perspectives. Curr Mol Med 2011;11:373-390.
10. Syed GH, Amako Y, Siddiqui A. Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab 2010;21:33-40.
11. Moriya K, Yotsuyanagi H, Shintani Y, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 1997;78: 1527-1531.
12. 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 2005;50:1361-1371.
13. Kim KH, Hong SP, Kim K, et al. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. Biochem Biophys Res Commun 2007;355:883-888.
14. Kim K, Kim KH, Ha E, et al. Hepatitis C virus NS5A protein increases hepatic lipid accumulation via induction of activation and expression of PPARgamma. FEBS Lett 2009;583:2720-2726.
15. Waris G, Felmlee DJ, Negro F, et al. 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.
16. Oem JK, Jackel-Cram C, Li YP, et al. Activation of sterol regulatory element-binding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein. J Gen Virol 2008;89:1225-1230.
17. Repa JJ, Liang G, Ou J, et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 2000;14:2819-2830.
18. Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 2000;16:459-481.
19. Yoshikawa T, Shimano H, Amemiya-Kudo M, et al. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 2001; 21:2991-3000.
20. Kim TH, Kim H, Park JM, et al. Interrelationship between liver X receptor alpha, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma, and small heterodimer partner in the transcriptional regulation of glucokinase gene expression in liver. J Biol Chem 2009;29:15071-15083.
21. Lima-Cabello E, Garća-Mediavilla MV, Miquilena-Colina ME, et al. Enhanced expression of pro-inflammatory mediators and liver Xreceptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. Clin Sci (Lond) 2011;120:239-250.
22. Miquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 2011;60:1394-1402.
23. Moriishi K, Mochizuki R, Moriya K, et al. Critical role of pa28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci USA 2007;104:1661-1666.
24. Su AI, Pezacki JP, Wodicka L, et al. Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci USA 2002; 99:15669-15674.
25. Kapadia SB, Chisari FV. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA 2005;102:2516-2566.
26. Yang W, Hood BL, Chadwick SL, et al. Fatty acid synthase is upregulated during hepatitis C virus infection and regulates hepatitis C virus entry and production. Hepatology 2008;48:1396-1403.
27. Syed GH, Siddiqui A. Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus. Hepatology 2011;54:1936-1946.
28. Zhu N, Khoshnan A, Schneider R, et al. Hepatitis C virus core protein binds to the cytoplasmatic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 1998;72: 3691-3697.
29. Núñ ez O, Fernández-Mart́nez A, Majano PL, et al. Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins. Gut 2004;53:1665-1672.
30. Benedicto I, Molina-Jiménez F, Barreiro O, et al. Hepatitis C virus envelope components alter localization of hepatocyte tight junctionassociated proteins and promote occludin retention in the endoplasmic reticulum. Hepatology 2008;48:1044-1053.
31. Dionisio N, Garća-Mediavilla MV, Sánchez-Campos S, et al. Hepatitis C virus NS5A and core proteins induce oxidative stress-mediated calcium signalling alterations in hepatocytes. J Hepatol 2009;50:872-882.
32. Garća-Mediavilla MV, Sánchez-Campos S, González- Pérez P, et al. Differential contribution of hepatitis C virus NS5A and core proteins to the induction of oxidative and nitrosative stress in human hepatocytederived cells. J Hepatol 2005;43:606-613.
33. Crespo I, Garća-Mediavilla MV, Gutiérrez B, et al. A comparison of the effects of kaempferol and quercetin on cytokine-induced proinflammatory status of cultured human endothelial cells. Br J Nutr 2008;100:968-976.
34. Borrás E, Zaragozá R, Morante M, et al. In vivo studies of altered expression patterns of p53 and proliferative control genes in chronic vitamin A deficiency and hypervitaminosis. Eur J Biochem 2003; 270:1493-1501.
35. Sandoval J, Rodŕguez JL, Tur G, et al. RNAPol-ChIP: a novel application of chromatin immunoprecipitation to the analysis of real-time gene transcription. Nucleic Acids Res 2004;32:e88.
36. Negro F. Hepatitis C virus-induced steatosis: an overview. Dig Dis 2010;28:294-299.
37. Willy PJ, Umesono K, Ong ES, et al. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 1995;9:1033-1045.
38. Joseph SB, Laffitte BA, Patel PH, et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 2002;277:11019-11025.
39. Horton JD, Goldstein JL, Brown MS. SREBPs: transcriptional mediators of lipid homeostasis. Cold Spring Harb Symp Quant Biol 2002;67: 491-498.
40. Moriishi K, Mochizuki R, Moriya K, et al. Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci USA 2007;104:1661-1666.
41. Xiang Z, Qiao L, Zhou Y, et al. Hepatitis C virus nonstructural protein-5A activates sterol regulatory element-binding protein-1c through transcription factor Sp1. Biochem Biophys Res Commun 2010;402: 549-553.
42. Kim K, Kim KH, Kim HH, et al. Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXR alpha. Biochem J 2008;416: 219-230.
43. Na TY, Shin YK, Roh KJ, et al. Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009;49:1122-1131.
44. Barba G, Harper F, Harada T, et al. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA 1997;94:1200-1205.
45. Shi ST, Polyak SJ, Tu H, et al. Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. Virology 2002;292:198-210.
46. Jackel-Cram C, Qiao L, Xiang Z, 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.
47. He Y, Nakao H, Tan SL, et al. Subversion of cell signaling pathways by hepatitis C virus nonstructural 5A protein via interaction with Grb2 and P85 phosphatidylinositol 3-kinase. J Virol 2002;76:9207-9217.
48. Street A, Macdonald A, Crowder K, et al. The Hepatitis C virus NS5A protein activates a phosphoinositide 3-kinase-dependent survival signaling cascade. J Biol Chem 2004;279:12232-12241.
49. Park CY, Jun HJ, Wakita T, et al. Hepatitis C virus non-structural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway. J Biol Chem 2009;284:9237-9246.
50. Huwait EA, Greenow KR, Singh NN, et al. A novel role for c-Jun Nterminal kinase and phosphoinositide 3-kinase in the liver X receptormediated induction of macrophage gene expression. Cell Signal 2011;23:542-549.
51. Ryan MC, Desmond PV, Slavin JL, et al. 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.
52. Kim K, Kim KH, Kim HY, et al. Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway. FEBS Lett 2010;584:707-712.
53. Mitro N, Vargas L, Romeo R, et al. T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett 2007;581: 1721-1726.