Recovery of pan-genotypic and genotype-specific amino acid alterations in chronic hepatitis C after viral clearance: transition at the crossroad of metabolism and immunity
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Recovery of amino acid (AA) metabolism and the associated clinical implications in chronic hepatitis C (CHC) patients with sustained virological response (SVR) following anti-hepatitis C virus (HCV) therapy remains elusive. A prospective cohort study was conducted on 222 CHC patients with SVR. Eighty-two age-matched male genotype 1 (G1) and G2 patients underwent paired serum metabolomics analyses with liquid chromatography–tandem mass spectrometry to examine AAs before and 24 weeks after anti-HCV therapy. Before anti-HCV therapy, G1 patients had a higher HCV RNA level than G2 patients. Twenty-four weeks post-therapy versus pre-therapy, repeated-measures ANOVA showed that the levels of alanine aminotransferase and most AAs decreased while those of lipids, glutamine and putrescine increased in CHC patients. The methionine sulfoxide/methionine ratio decreased, while the asymmetric dimethylarginine/arginine, glutamine/glutamate, citrulline/arginine, ornithine/arginine, kynurenine/tryptophan, tyrosine/phenylalanine and Fisher’s ratios increased. Genotype-specific subgroup analyses showed that valine and serotonin/tyrosine increased in G1 and that kynurenine and tyrosine/phenylalanine increased and sarcosine decreased in G2 patients. Viral clearance in CHC patients pan-genotypically restored fuel utilization by decelerating the tricarboxylic acid cycle. Following improvement in liver function, the urea, nitric oxide, methionine, and polyamine cycles were accelerated. The cardiometabolic risk attenuated, but the augmented kynurenine pathway activity could increase the oncogenesis risk. The trends in neurotransmitter formation differed between G1 and G2 patients after SVR. Moreover, the HCV-suppressing effect of valine was evident in G1 patients; with the exception of prostate cancer, the oncogenesis risk increased, particularly in G2 patients, at least within 24 weeks post-anti-HCV therapy.
KeywordsHCV Genotype Amino acids Targeted metabolomics LC–MS/MS
The authors thank Mr. Cheng-Yu Huang from Metabolomics Core Laboratory, Health Aging Research Center, Chang Gung University and Mr. Chun-Ming Fan from the Department of Biomedical Sciences, College of Medicine, Chang Gung University for their excellent figure generations and Ms. Shu-Chun Chen from the Liver Research Center, Chang Gung Memorial Hospital, Taiwan, for her data mining assistance.
Compliance with ethical standards
This study was supported by grants from the Chang Gung Medical Research Program (CIRPG3D0121, CMRPG3F0471, CRRPG3F0011, CMRPG3B1743 and XMRPG3A0525) and from the National Science Council, Taiwan (102-2628-B-182-021-MY3, MOST 105-2314-B-182-023, and MOST 105-2629-B-182-001-).
Conflict of interest
The authors declare that they have no conflict of interest.
- Boulet MM, Chevrier G, Grenier-Larouche T, Pelletier M, Nadeau M, Scarpa J, Prehn C, Marette A, Adamski J, Tchernof A (2015) Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk. Am J Physiol Endocrinol Metab 309:E736–E746CrossRefPubMedGoogle Scholar
- Chang ML, Tsou YK, Hu TH, Lin CH, Lin WR, Sung CM, Chen TH, Cheng ML, Chang KC, Chiu CT, Yeh CT, Pang JH, Shiao MS (2014) Distinct patterns of the lipid alterations between genotype 1 and 2 chronic hepatitis C patients after viral clearance. PLoS One 9:e104783CrossRefPubMedPubMedCentralGoogle Scholar
- Cheng S, Rhee EP, Larson MG, Lewis GD, McCabe EL, Shen D, Palma MJ, Roberts LD, Dejam A, Souza AL, Deik AA, Magnusson M, Fox CS, O’Donnell CJ, Vasan RS, Melander O, Clish CB, Gerszten RE, Wang TJ (2012) Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 125:2222–2231CrossRefPubMedPubMedCentralGoogle Scholar
- Saito T, Sugimoto M, Igarashi K, Saito K, Shao L, Katsumi T, Tomita K, Sato C, Okumoto K, Nishise Y, Watanabe H, Tomita M, Ueno Y, Soga T (2013) Dynamics of serum metabolites in patients with chronic hepatitis C receiving pegylated interferon plus ribavirin: a metabolomics analysis. Metabolism 62:1577–1586CrossRefPubMedGoogle Scholar
- Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457:910–914CrossRefPubMedPubMedCentralGoogle Scholar
- Sugiyama K, Ebinuma H, Nakamoto N, Sakasegawa N, Murakami Y, Chu PS, Usui S, Ishibashi Y, Wakayama Y, Taniki N, Murata H, Saito Y, Fukasawa M, Saito K, Yamagishi Y, Wakita T, Takaku H, Hibi T, Saito H, Kanai T (2014) Prominent steatosis with hypermetabolism of the cell line permissive for years of infection with hepatitis C virus. PLoS One 9:e94460CrossRefPubMedPubMedCentralGoogle Scholar
- Toyoda H, Kumada T, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Ito T (2015) Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. J Gastroenterol Hepatol 30:1183–1189CrossRefPubMedGoogle Scholar
- Zhang AH, Sun H, Han Y, Yan GL, Yuan Y, Song GC, Yuan XX, Xie N, Wang XJ (2013) Ultraperformance liquid chromatography-mass spectrometry based comprehensive metabolomics combined with pattern recognition and network analysis methods for characterization of metabolites and metabolic pathways from biological data sets. Anal Chem 85:7606–7612CrossRefPubMedGoogle Scholar