Hepatocyte-Specific Triggering of Hepatic Stellate Cell Profibrotic Activation by Apoptotic Bodies: The Role of Hepatoma-Derived Growth Factor, HIV, and Ethanol
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Published:2023-03-10
Issue:6
Volume:24
Page:5346
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
New-Aaron Moses12ORCID, Koganti Siva Sankar23, Ganesan Murali23, Kanika Sharma4, Kumar Vikas4ORCID, Wang Weimin4, Makarov Edward4, Kharbanda Kusum K.23ORCID, Poluektova Larisa Y.5ORCID, Osna Natalia A.1235ORCID
Affiliation:
1. Department of Environmental Health, Occupational Health and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA 2. Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA 3. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA 4. Department of Genetics Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68105, USA 5. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USA
Abstract
Liver disease is one of the leading comorbidities in HIV infection. The risk of liver fibrosis development is potentiated by alcohol abuse. In our previous studies, we reported that hepatocytes exposed to HIV and acetaldehyde undergo significant apoptosis, and the engulfment of apoptotic bodies (ABs) by hepatic stellate cells (HSC) potentiates their pro-fibrotic activation. However, in addition to hepatocytes, under the same conditions, ABs can be generated from liver-infiltrating immune cells. The goal of this study is to explore whether lymphocyte-derived ABs trigger HSC profibrotic activation as strongly as hepatocyte-derived ABs. ABs were generated from Huh7.5-CYP2E1 (RLW) cells and Jurkat cells treated with HIV+acetaldehyde and co-culture with HSC to induce their pro-fibrotic activation. ABs cargo was analyzed by proteomics. ABs generated from RLW, but not from Jurkat cells activated fibrogenic genes in HSC. This was driven by the expression of hepatocyte-specific proteins in ABs cargo. One of these proteins is Hepatocyte-Derived Growth Factor, for which suppression attenuates pro-fibrotic activation of HSC. In mice humanized with only immune cells but not human hepatocytes, infected with HIV and fed ethanol, liver fibrosis was not observed. We conclude that HIV+ABs of hepatocyte origin promote HSC activation, which potentially may lead to liver fibrosis progression.
Funder
National Institute of Health
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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