HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.

Autor: Cheng Y; Department of Biomedical and Translational Sciences, Macro & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA., Jung J; Department of Biomedical and Translational Sciences, Macro & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA., Guo L; Department of Biomedical and Translational Sciences, Macro & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA., Shuboni-Mulligan DD; Department of Biomedical and Translational Sciences, Macro & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA., Chen JF; Center for Craniofacial Molecular Biology, University of Southern California (USC), Los Angeles, CA 90033, USA., Hu W; Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA., Guo ML; Department of Biomedical and Translational Sciences, Macro & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; Center for Integrative Neuroscience and Inflammatory Diseases, Macro & Joan Brock Virginia Health Science, Old Dominion University, Norfolk, VA 23507, USA. Electronic address: GuoM@Odu.edu.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2024 Sep 10; Vol. 123, pp. 108-122. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1016/j.bbi.2024.09.011
Abstrakt: Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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