Elevated Autotaxin and LPA Levels during Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation

Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC).

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Faculty Opinions recommendation of Microbial translocation is a cause of systemic immune activation in chronic HIV infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1053670.505848 ◽

2006 ◽

Author(s):

Christopher Karp

Keyword(s):

Hiv Infection ◽

Immune Activation ◽

Microbial Translocation ◽

Systemic Immune Activation ◽

Chronic Hiv Infection

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Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

International Journal of Molecular Sciences ◽

10.3390/ijms23010500 ◽

2022 ◽

Vol 23 (1) ◽

pp. 500

Author(s):

Francesco Paolo Russo ◽

Alberto Zanetto ◽

Elisa Pinto ◽

Sara Battistella ◽

Barbara Penzo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Viral Hepatitis ◽

Chronic Viral Hepatitis ◽

Virological Suppression ◽

Risk Patients ◽

Related Liver Disease ◽

Direct Acting ◽

Cell Signaling Pathways

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in “high-risk” patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient’s risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.

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Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma

Gut ◽

10.1136/gutjnl-2019-318918 ◽

2020 ◽

Vol 70 (1) ◽

pp. 157-169 ◽

Cited By ~ 3

Author(s):

Frank Jühling ◽

Nourdine Hamdane ◽

Emilie Crouchet ◽

Shen Li ◽

Houssein El Saghire ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Ex Vivo ◽

Treatment Options ◽

Cancer Chemoprevention ◽

Chronic Viral Hepatitis ◽

Epigenetic Modifications ◽

System Modelling ◽

Epigenetic Alterations ◽

Transcriptional Reprogramming

ObjectiveHepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.DesignLiver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention.ResultsIn patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.ConclusionOur results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.

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