Cocaine and HIV‐1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV‐associated neurocognitive disorders in cocaine user patients
Open accessAbstract
Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP‐binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV‐associated neurocognitive disorders (HAND) and in cocaine‐mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV‐Tat significantly decreases LXRβ levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.
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HIV infection or HIV proteins dysregulate lipid and cholesterol metabolism in the central nervous system and promote the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV.
“Additionally, HIV infection or HIV proteins have been shown to dysregulate lipid and cholesterol metabolism in the central nervous system (CNS) and promote the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV [10, 11].”
From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [11]
The Results (page unavailable) show that HIV-1 Tat reduced cholesterol levels and cholesterol release in cultured astrocytes, supporting the metabolism finding for an HIV protein. But the Abstract and Introduction describe a possible contribution to HAND, not a demonstrated promotion of its pathogenesis; the findings also do not establish the claim for HIV infection generally. (LLM, conf=0.86)
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BackgroundCortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine
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BackgroundEffect of cholesterol reduction on receptor signaling in neurons.
Fukui, K., Ferris, H. A., & Kahn, C. R. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.a115.664367 · Cited by 11 · see citing works
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HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System
Nickoloff-Bybel, E. A., Calderon, T. M., Gaskill, P. J., & Berman, J. W. (2020) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-020-09927-6 · Cited by 41 · see citing works
Mohseni Ahooyi, T., Shekarabi, M., Torkzaban, B., Langford, T. D., Burdo, T. H., Gordon, J., Datta, P. K., Amini, S., & Khalili, K. (2018) · Scientific Reports · doi:10.1038/s41598-018-34539-9 · Cited by 29 · see citing works
Cirino, T. J., Harden, S. W., McLaughlin, J. P., & Frazier, C. J. (2020) · Journal of Neurophysiology · doi:10.1152/jn.00029.2020 · Cited by 26 · see citing works
DeMarino, C., Cowen, M., Khatkar, P., Cotto, B., Branscome, H., Kim, Y., Sharif, S. A., Agbottah, E. T., Zhou, W., Costiniuk, C. T., et al. (2022) · Cells · doi:10.3390/cells11040723 · Cited by 27 · see citing works
“Cell viability was determined by the formation of formazan crystal and measured by absorbance at 590 nm and 620 nm, as previously described [26].”
MethodSelf-citationParis, J. J., Lière, P., Kim, S., Mahdi, F., Buchanan, M. E., Nass, S. R., Qrareya, A. N., Mohammed, S., Pianos, A., Fernandez, N., et al. (2020) · Neurobiology of Stress · doi:10.1016/j.ynstr.2020.100211 · Cited by 26 · see citing works
“Opposing effects for Tat (with or without cocaine) to reduce intra- and extracellular cholesterol in astrocytes have also been observed (Cotto et al., 2018), supporting the notion of dynamic changes in central cholesterol bioavailability following exposure to Tat and psychostimulants.”
Mohammed, S., Mahdi, F., & Paris, J. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218212 · Cited by 24 · see citing works
“Tat protein is sufficient to dysregulate gene expression associated with lipid and cholesterol trafficking and homeostasis [40,41] and increases the production of ceramides that inhibit steroidogenic enzymes [42].”
BackgroundQrareya, A. N., Mahdi, F., Kaufman, M. J., Ashpole, N. M., & Paris, J. J. (2020) · GeroScience · doi:10.1007/s11357-020-00268-z · Cited by 19 · see citing works
Cheng, Y., Jung, J., Guo, L., Shuboni-Mulligan, D. D., Chen, J.-F., Hu, W., & Guo, M.-L. (2025) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2024.09.011 · Cited by 16 · see citing works
The lncRNA LOC102549805 (U1) modulates neurotoxicity of HIV-1 Tat protein
Torkzaban, B., Natarajaseenivasan, K., Ahooyi, T. M., Shekarabi, M., Amini, S., Langford, D., & Khalili, K. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-03033-4 · Cited by 16 · see citing works
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Natarajaseenivasan, K., Shanmughapriya, S., Velusamy, P., Sayre, M., Garcia, A., Gomez, N. M., & Langford, D. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00211-4 · Cited by 15 · see citing works
Self-citationQrareya, A. N., Mahdi, F., Kaufman, M. J., Ashpole, N. M., & Paris, J. J. (2022) · Aging · doi:10.18632/aging.204166 · Cited by 10 · see citing works
The Epigenetic Role of miR-124 in HIV-1 Tat- and Cocaine-Mediated Microglial Activation
Periyasamy, P., Thangaraj, A., Kannan, M., Oladapo, A., & Buch, S. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315017 · Cited by 10 · see citing works
Mohammed, S., Qrareya, A. N., Mahdi, F., Moss, E. M., Akins, N. S., Li, J., Le, H. V., & Paris, J. J. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.13047 · Cited by 8 · see citing works
Exposure to Morphine and Cocaine Modify the Transcriptomic Landscape in Zebrafish Embryos
Calderón‐García, A. Á., Perez-Fernandez, M., Curto-Aguilera, D., Rodríguez-Martín, I., Sánchez‐Barba, M., & González-Núñez, V. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.10.017 · Cited by 8 · see citing works
“In transgenic mice that express Tat protein (a transactivator required for HIV replication), cocaine exposure has been shown to decrease LXRb receptor levels, as well as the expression of its target genes; as a consequence, the bioavailability of cholesterol in the brain of these mice is increased (Cotto et al., 2018).”
BackgroundTorkzaban, B., Ahooyi, T. M., Duggan, M. R., Amini, S., & Khalili, K. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104880 · Cited by 8 · see citing works
“Along with ceramide and sphingomyelin, the dysregulation of cholesterol metabolism in both neuronal and non-neuronal cells following HIV infection has been studied extensively (Cotto et al., 2018; DeLucia et al., 2018; Mujawar et al., 2006; Sviridov et al., 2020) (Zangerle et al.”
BackgroundInfluentialNatarajaseenivasan, K., Garcia, A., Velusamy, P., Shanmughapriya, S., & Langford, D. (2022) · iScience · doi:10.1016/j.isci.2022.105407 · Cited by 6 · see citing works
“…peroxidation of FA in neurons, we exposed neurons to HIV-1 MN Tat (50 ng/mL), cocaine (5mM), or both every 24 h for 48 h, as previously reported (Kovalevich, 2012a; Kovalevich et al., 2012b; Kovalevich, 2015; Cotto et al., 2018b; Mohseni Ahooyi T et al., 2018; Natarajaseenivasan et al., 2018).”
InfluentialSelf-citationAstrocytes: Role in pathogenesis and effect of commonly misused drugs in the HIV infected brain
Pla-Tenorio, J., Roig, A. M., García-Cesaní, P. A., Santiago, L. A., Sepulveda-Orengo, M. T., & Noel, R. J. (2023) · Current Research in Neurobiology · doi:10.1016/j.crneur.2023.100108 · Cited by 6 · see citing works
“HIV and drugs like opioids and meth have been to synergistically disrupt the BBB (Mahajan et al., 2008a) facilitating infected monocyte transmigration (Cotto et al., 2018) and inducing a neuroinflammation process that leads to cognitive decline (Chilunda et al., 2019).”
BackgroundInfluentialQiu, X., Wang, J., Zhang, W., Duan, C., Chen, T., Zhang, D., Su, J., & Gao, L. (2023) · Journal of NeuroVirology · doi:10.1007/s13365-023-01131-5 · Cited by 4 · see citing works
Spatial Heterogeneity of Brain Lipids in SIV-Infected Macaques Treated with Antiretroviral Therapy
White, C. J., Gausepohl, A. M., Wilkins, H. N., Eberhard, C. D., Orsburn, B. C., & Williams, D. W. (2024) · Journal of the American Society for Mass Spectrometry · doi:10.1021/jasms.3c00276 · Cited by 4 · see citing works
Carbone, M. G., Maremmani, I., Rocca, F. D., Gastaldello, G., Mazzetto, L., Bellini, A., Rizzato, R., Miccichè, R., Tripodi, B., Tagliarini, C., et al. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15062222 · Cited by 3 · see citing works
Tice, C. M., Zhao, H., & Langford, D. (2023) · Journal of NeuroVirology · doi:10.1007/s13365-023-01126-2 · Cited by 3 · see citing works
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Shanmughapriya, S., Ahooyi, T. M., Torkzaban, B., Garikipati, V. N. S., Kishore, R., Khallili, K., Langford, D., & Natarajaseenivasan, K. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02589-y · Cited by 2 · see citing works
“In our research, astrocytes were treated with factors known to induce a reactive phenotype, whereby they entered a hypermetabolic state [11, 12].”
Self-citationWhite, C. J., & Goodkin, K. (2023) · AIDS · doi:10.1097/qad.0000000000003535 · Cited by 2 · see citing works
Franklin, J. P., Testen, A., Mieczkowski, P. A., Hepperla, A. J., Crynen, G. C., Simon, J. M., Wood, J., Harder, E. V., Bellinger, T. J., Witt, E. A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.05.606656 · Cited by 1 · see citing works
Zhao, X., Zhang, F., Kandel, S. R., Brau, F., & He, J. J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.11.22.469603
“Tat and cocaine alter metabolism [57-60] and increase the blood brain barrier permeability [61-63].”
BackgroundResultZhao, X., Zhang, F., Kandel, S. R., Brau, F., & He, J. J. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3985171
The role of HIV-associated neuroendocrine dysfunction in HAND
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Fat on Fire: Disrupted Microglial Lipid Metabolism as a Driver of Anesthetic Neurotoxicity
Mou, Y., Tu, H., Yi-chan, W., Song, S.-Y., Liu, H., Wang, D., Wu, J., Meng, X., Qin, Z.-H., & Ji, F.-H. (2026) · Neuroscience Bulletin · doi:10.1007/s12264-026-01623-4
“Similarly, in vitro studies report that cocaine impairs astrocyte-derived cholesterol export by suppressing ABCA1 and APOE, which in turn compromises neuronal cholesterol supply [63].”
- Authors
- Cotto, B., Natarajaseenivasan, K., Ferrero, K., Wesley, L., Sayre, M., & Langford, D.
- Affiliations
- Temple University (US)
- Corresponding author
- Langford, Dianne
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2018-01-13
- Volume
- 66
- Issue
- 4
- Pages
- 889-902
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC5769965
- OpenAlex
- W2782945233
- Cited by
- 30
- References
- 60
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 8 · 2018: 1
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P01DA037830, P30MH09217, T32MH079785, R25MH080661‐11)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cocaine, HIV-1 Tat protein, astrocytes, cholesterol homeostasis, liver X receptor, LXRβ, HIV-associated neurocognitive disorders, cocaine use, cholesterol metabolism, neurocognitive impairment, brain energy metabolism
- MeSH terms
- Liver X Receptors, Animals, Astrocytes, Brain, Cells, Cultured, Cholesterol, Cocaine, Disease Models, Animal, Female, Homeostasis, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, HIV-1, AIDS Dementia Complex, Dopamine Uptake Inhibitors, Cocaine-Related Disorders, tat Gene Products, Human Immunodeficiency Virus
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