Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures
Combined antiretroviral therapy (cART) has greatly decreased mortality and morbidity among persons with HIV; however, neurologic impairments remain prevalent, in particular HIV-associated neurocognitive disorders (HANDs). White matter damage persists in cART-treated persons with HIV and may contribu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1323431/full |
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| author | Hubert Monnerie Micah Romer Lindsay M. Roth Caela Long John S. Millar Kelly L. Jordan-Sciutto Judith B. Grinspan |
| author_facet | Hubert Monnerie Micah Romer Lindsay M. Roth Caela Long John S. Millar Kelly L. Jordan-Sciutto Judith B. Grinspan |
| author_sort | Hubert Monnerie |
| collection | DOAJ |
| description | Combined antiretroviral therapy (cART) has greatly decreased mortality and morbidity among persons with HIV; however, neurologic impairments remain prevalent, in particular HIV-associated neurocognitive disorders (HANDs). White matter damage persists in cART-treated persons with HIV and may contribute to neurocognitive dysfunction as the lipid-rich myelin membrane of oligodendrocytes is essential for efficient nerve conduction. Because of the importance of lipids to proper myelination, we examined the regulation of lipid synthesis in oligodendrocyte cultures exposed to the integrase strand transfer inhibitor elvitegravir (EVG), which is administered to persons with HIV as part of their initial regimen. We show that protein levels of genes involved in the fatty acid pathway were reduced, which correlated with greatly diminished de novo levels of fatty acid synthesis. In addition, major regulators of cellular lipid metabolism, the sterol regulatory element-binding proteins (SREBP) 1 and 2, were strikingly altered following exposure to EVG. Impaired oligodendrocyte differentiation manifested as a marked reduction in mature oligodendrocytes. Interestingly, most of these deleterious effects could be prevented by adding serum albumin, a clinically approved neuroprotectant. These new findings, together with our previous study, strengthen the possibility that antiretroviral therapy, at least partially through lipid dysregulation, may contribute to the persistence of white matter changes observed in persons with HIV and that some antiretrovirals may be preferable as life-long therapy. |
| first_indexed | 2024-03-09T01:12:06Z |
| format | Article |
| id | doaj.art-d47bdc2e2ecf4e7fa6028db6e43612a6 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-09T01:12:06Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-d47bdc2e2ecf4e7fa6028db6e43612a62023-12-11T04:28:43ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-12-011610.3389/fnmol.2023.13234311323431Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte culturesHubert Monnerie0Micah Romer1Lindsay M. Roth2Caela Long3John S. Millar4Kelly L. Jordan-Sciutto5Judith B. Grinspan6Department of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesInstitute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesCombined antiretroviral therapy (cART) has greatly decreased mortality and morbidity among persons with HIV; however, neurologic impairments remain prevalent, in particular HIV-associated neurocognitive disorders (HANDs). White matter damage persists in cART-treated persons with HIV and may contribute to neurocognitive dysfunction as the lipid-rich myelin membrane of oligodendrocytes is essential for efficient nerve conduction. Because of the importance of lipids to proper myelination, we examined the regulation of lipid synthesis in oligodendrocyte cultures exposed to the integrase strand transfer inhibitor elvitegravir (EVG), which is administered to persons with HIV as part of their initial regimen. We show that protein levels of genes involved in the fatty acid pathway were reduced, which correlated with greatly diminished de novo levels of fatty acid synthesis. In addition, major regulators of cellular lipid metabolism, the sterol regulatory element-binding proteins (SREBP) 1 and 2, were strikingly altered following exposure to EVG. Impaired oligodendrocyte differentiation manifested as a marked reduction in mature oligodendrocytes. Interestingly, most of these deleterious effects could be prevented by adding serum albumin, a clinically approved neuroprotectant. These new findings, together with our previous study, strengthen the possibility that antiretroviral therapy, at least partially through lipid dysregulation, may contribute to the persistence of white matter changes observed in persons with HIV and that some antiretrovirals may be preferable as life-long therapy.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1323431/fullcARTHandHIVmyelinoligodendrocyteSREBP |
| spellingShingle | Hubert Monnerie Micah Romer Lindsay M. Roth Caela Long John S. Millar Kelly L. Jordan-Sciutto Judith B. Grinspan Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures Frontiers in Molecular Neuroscience cART Hand HIV myelin oligodendrocyte SREBP |
| title | Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures |
| title_full | Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures |
| title_fullStr | Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures |
| title_full_unstemmed | Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures |
| title_short | Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures |
| title_sort | inhibition of lipid synthesis by the hiv integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures |
| topic | cART Hand HIV myelin oligodendrocyte SREBP |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1323431/full |
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