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Altered pattern of circulating miRNAs in HIV lipodystrophy perturbs key adipose differentiation and inflammation pathways
Suman Srinivasa, … , C. Ronald Kahn, Steven K. Grinspoon
Suman Srinivasa, … , C. Ronald Kahn, Steven K. Grinspoon
Published August 12, 2021
Citation Information: JCI Insight. 2021;6(18):e150399. https://doi.org/10.1172/jci.insight.150399.
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Research Article AIDS/HIV Endocrinology

Altered pattern of circulating miRNAs in HIV lipodystrophy perturbs key adipose differentiation and inflammation pathways

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Abstract

We identified a microRNA (miRNA) profile characterizing HIV lipodystrophy and explored the downstream mechanistic implications with respect to adipocyte biology and the associated clinical phenotype. miRNA profiles were extracted from small extracellular vesicles (sEVs) of HIV-infected individuals with and without lipodystrophic changes and individuals without HIV, among whom we previously showed significant reductions in adipose Dicer expression related to HIV. miR-20a-3p was increased and miR-324-5p and miR-186 were reduced in sEVs from HIV lipodystrophic individuals. Changes in these miRNAs correlated with adipose Dicer expression and clinical markers of lipodystrophy, including fat redistribution, insulin resistance, and hypertriglyceridemia. Human preadipocytes transfected with mimic miR-20a-3p, anti–miR-324-5p, or anti–miR-186 induced consistent changes in latent transforming growth factor beta binding protein 2 (Ltbp2), Wisp2, and Nebl expression. Knockdown of Ltbp2 downregulated markers of adipocyte differentiation (Fabp4, Pparγ, C/ebpa, Fasn, adiponectin, Glut4, CD36), and Lamin C, and increased expression of genes involved in inflammation (IL1β, IL6, and Ccl20). Our studies suggest a likely unique sEV miRNA signature related to dysregulation of Dicer in adipose tissue in HIV. Enhanced miR-20a-3p or depletion of miR-186 and miR-324-5p may downregulate Ltbp2 in HIV, leading to dysregulation in adipose differentiation and inflammation, which could contribute to acquired HIV lipodystrophy and associated metabolic and inflammatory perturbations.

Authors

Suman Srinivasa, Ruben Garcia-Martin, Martin Torriani, Kathleen V. Fitch, Anna R. Carlson, C. Ronald Kahn, Steven K. Grinspoon

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Figure 3

Expression of miR-20a-3p in alternative models of reduced Dicer expression.

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Expression of miR-20a-3p in alternative models of reduced Dicer expressi...
(A) Normalized sEV miRNA expression for miR-20a-3p in aDicer-KO mice versus control. (B) Normalized sEV miRNA expression for miR-20a-3p in adipocytes transfected with Dicer siRNA versus control. Data are expressed as mean ± SEM. *P < 0.05. n = 5 sera pools for control mouse group (each pool derives from sera of 3 mice), n = 3 sera pools for aDicer-KO mouse group (each pool derives from sera of 3 mice), n = 3 per group applies for B. ND, not detected.

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