Hepatocyte-Specific Triggering of Hepatic Stellate Cell Profibrotic Activation by Apoptotic Bodies: The Role of Hepatoma-Derived Growth Factor, HIV, and Ethanol

• Published in: International journal of molecular sciences Vol. 24; no. 6; p. 5346
• Main Authors: New-Aaron, Moses, Koganti, Siva Sankar, Ganesan, Murali, Kanika, Sharma, Kumar, Vikas, Wang, Weimin, Makarov, Edward, Kharbanda, Kusum K, Poluektova, Larisa Y, Osna, Natalia A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2023; MDPI
• Subjects: Acetaldehyde; Acetaldehyde - metabolism; Acquired immune deficiency syndrome; AIDS; Alcohol; Alcohol abuse; Alcohol, Denatured; Alcoholism; Animals; Apoptosis; apoptotic bodies; Cell activation; Cell culture; Comorbidity; Drug abuse; Ethanol; Ethanol - metabolism; Extracellular Vesicles - metabolism; Fibrosis; Growth factors; HDGF; Health aspects; hepatic stellate cells; Hepatic Stellate Cells - metabolism; Hepatocytes; Hepatocytes - metabolism; Hepatoma; HIV; HIV (Viruses); HIV infection; HIV Infections - metabolism; Human immunodeficiency virus; Immune system; Infection; Intercellular Signaling Peptides and Proteins - metabolism; Liver; Liver - metabolism; Liver cancer; Liver Cirrhosis - metabolism; Liver diseases; liver fibrosis; Lymphocytes; Mice; Proteins; Proteomics; Scientific equipment and supplies industry; Stellate cells; United States; Massachusetts; Nebraska; alcohol; hepatic stellate cells; liver fibrosis; HDGF; HIV; apoptotic bodies
• DOI: 10.3390/ijms24065346
• ISSN: 1422-0067; 1661-6596

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.