Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells
Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored “second hit” for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We ex...
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MDPI AG
2021-10-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/10/1497 |
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| author | Moses New-Aaron Paul G. Thomes Murali Ganesan Raghubendra Singh Dagur Terrence M. Donohue Kharbanda K. Kusum Larisa Y. Poluektova Natalia A. Osna |
| author_facet | Moses New-Aaron Paul G. Thomes Murali Ganesan Raghubendra Singh Dagur Terrence M. Donohue Kharbanda K. Kusum Larisa Y. Poluektova Natalia A. Osna |
| author_sort | Moses New-Aaron |
| collection | DOAJ |
| description | Although the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored “second hit” for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also known as RLW) cells to an acetaldehyde-generating system (AGS) for 24 h. We then infected (or not) the cells with HIV-1<sub>ADA</sub> then exposed them again to AGS for another 48 h. Lysosome damage was assessed by galectin 3/LAMP1 co-localization and cathepsin leakage. Expression of lysosome biogenesis–transcription factor, TFEB, was measured by its protein levels and by in situ immunofluorescence. Exposure of cells to both AGS + HIV caused the greatest amount of lysosome leakage and its impaired lysosomal biogenesis, leading to intrinsic apoptosis. Furthermore, the movement of TFEB from cytosol to the nucleus via microtubules was impaired by AGS exposure. The latter impairment appeared to occur by acetylation of α-tubulin. Moreover, ZKSCAN3, a repressor of lysosome gene activation by TFEB, was amplified by AGS. Both these changes contributed to AGS-elicited disruption of lysosome biogenesis. Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby exacerbating HIV-induced hepatotoxicity. |
| first_indexed | 2024-03-10T06:42:50Z |
| format | Article |
| id | doaj.art-dd84d8c1002949b4a33f08ac250a2f9a |
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| language | English |
| last_indexed | 2024-03-10T06:42:50Z |
| publishDate | 2021-10-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-dd84d8c1002949b4a33f08ac250a2f9a2023-11-22T17:34:30ZengMDPI AGBiomolecules2218-273X2021-10-011110149710.3390/biom11101497Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver CellsMoses New-Aaron0Paul G. Thomes1Murali Ganesan2Raghubendra Singh Dagur3Terrence M. Donohue4Kharbanda K. Kusum5Larisa Y. Poluektova6Natalia A. Osna7Department of Environmental Health, Occupational Health, and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USAResearch Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USADepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68105, USADepartment of Environmental Health, Occupational Health, and Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USAAlthough the causes of hepatotoxicity among alcohol-abusing HIV patients are multifactorial, alcohol remains the least explored “second hit” for HIV-related hepatotoxicity. Here, we investigated whether metabolically derived acetaldehyde impairs lysosomes to enhance HIV-induced hepatotoxicity. We exposed Cytochrome P450 2E1 (CYP2E1)-expressing Huh 7.5 (also known as RLW) cells to an acetaldehyde-generating system (AGS) for 24 h. We then infected (or not) the cells with HIV-1<sub>ADA</sub> then exposed them again to AGS for another 48 h. Lysosome damage was assessed by galectin 3/LAMP1 co-localization and cathepsin leakage. Expression of lysosome biogenesis–transcription factor, TFEB, was measured by its protein levels and by in situ immunofluorescence. Exposure of cells to both AGS + HIV caused the greatest amount of lysosome leakage and its impaired lysosomal biogenesis, leading to intrinsic apoptosis. Furthermore, the movement of TFEB from cytosol to the nucleus via microtubules was impaired by AGS exposure. The latter impairment appeared to occur by acetylation of α-tubulin. Moreover, ZKSCAN3, a repressor of lysosome gene activation by TFEB, was amplified by AGS. Both these changes contributed to AGS-elicited disruption of lysosome biogenesis. Our findings indicate that metabolically generated acetaldehyde damages lysosomes and likely prevents their repair and restoration, thereby exacerbating HIV-induced hepatotoxicity.https://www.mdpi.com/2218-273X/11/10/1497lysosome damagelysosome biogenesisHIVethanol metaboliteshepatotoxicity |
| spellingShingle | Moses New-Aaron Paul G. Thomes Murali Ganesan Raghubendra Singh Dagur Terrence M. Donohue Kharbanda K. Kusum Larisa Y. Poluektova Natalia A. Osna Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells Biomolecules lysosome damage lysosome biogenesis HIV ethanol metabolites hepatotoxicity |
| title | Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells |
| title_full | Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells |
| title_fullStr | Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells |
| title_full_unstemmed | Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells |
| title_short | Alcohol-Induced Lysosomal Damage and Suppression of Lysosome Biogenesis Contribute to Hepatotoxicity in HIV-Exposed Liver Cells |
| title_sort | alcohol induced lysosomal damage and suppression of lysosome biogenesis contribute to hepatotoxicity in hiv exposed liver cells |
| topic | lysosome damage lysosome biogenesis HIV ethanol metabolites hepatotoxicity |
| url | https://www.mdpi.com/2218-273X/11/10/1497 |
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