Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.
BACKGROUND AND AIMS: Chronic hepatitis C is a global health problem with an estimated 170 million HCV infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes includ...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2017
|
| _version_ | 1797063384025268224 |
|---|---|
| author | Farquhar, M Humphreys, I Rudge, S Wilson, G Bhattacharya, B Ciaccia, M Hu, K Zhang, Q Mailly, L Reynolds, G Aschcroft, M Balfe, P Baumert, T Roessler, S Wakelam, M McKeating, J |
| author_facet | Farquhar, M Humphreys, I Rudge, S Wilson, G Bhattacharya, B Ciaccia, M Hu, K Zhang, Q Mailly, L Reynolds, G Aschcroft, M Balfe, P Baumert, T Roessler, S Wakelam, M McKeating, J |
| author_sort | Farquhar, M |
| collection | OXFORD |
| description | BACKGROUND AND AIMS: Chronic hepatitis C is a global health problem with an estimated 170 million HCV infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. <br/> <br/>METHODS: In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. <br/> <br/> RESULTS: HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumor tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF-signalling pathway abrogates the pro-viral activity of LPA. <br/> <br/>CONCLUSIONS: Our data support a model where HCV infection increases ATX expression that supports viral replication and HCC progression. <br/> <br/>LAY SUMMARY: Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that Hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication. |
| first_indexed | 2024-03-06T20:59:04Z |
| format | Journal article |
| id | oxford-uuid:3a419b71-51fb-47d3-b1ea-3cb2ceb98624 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:59:04Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:3a419b71-51fb-47d3-b1ea-3cb2ceb986242022-03-26T14:00:34ZAutotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3a419b71-51fb-47d3-b1ea-3cb2ceb98624EnglishSymplectic Elements at OxfordElsevier2017Farquhar, MHumphreys, IRudge, SWilson, GBhattacharya, BCiaccia, MHu, KZhang, QMailly, LReynolds, GAschcroft, MBalfe, PBaumert, TRoessler, SWakelam, MMcKeating, JBACKGROUND AND AIMS: Chronic hepatitis C is a global health problem with an estimated 170 million HCV infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. <br/> <br/>METHODS: In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. <br/> <br/> RESULTS: HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumor tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF-signalling pathway abrogates the pro-viral activity of LPA. <br/> <br/>CONCLUSIONS: Our data support a model where HCV infection increases ATX expression that supports viral replication and HCC progression. <br/> <br/>LAY SUMMARY: Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that Hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication. |
| spellingShingle | Farquhar, M Humphreys, I Rudge, S Wilson, G Bhattacharya, B Ciaccia, M Hu, K Zhang, Q Mailly, L Reynolds, G Aschcroft, M Balfe, P Baumert, T Roessler, S Wakelam, M McKeating, J Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. |
| title | Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. |
| title_full | Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. |
| title_fullStr | Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. |
| title_full_unstemmed | Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. |
| title_short | Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. |
| title_sort | autotaxin lysophosphatidic acid receptor signalling regulates hepatitis c virus replication |
| work_keys_str_mv | AT farquharm autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT humphreysi autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT rudges autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT wilsong autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT bhattacharyab autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT ciacciam autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT huk autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT zhangq autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT maillyl autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT reynoldsg autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT aschcroftm autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT balfep autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT baumertt autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT roesslers autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT wakelamm autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication AT mckeatingj autotaxinlysophosphatidicacidreceptorsignallingregulateshepatitiscvirusreplication |