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

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 9

Hypothesized translational model of adipose dysfunction and metabolic complications in HIV lipodystrophy.

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Hypothesized translational model of adipose dysfunction and metabolic co...
Accessory proteins of the HIV may suppress Dicer expression in the adipose tissue. Lack of Dicer in adipose tissue leads to lipodystrophic changes in fat redistribution, metabolic dysregulation, and alteration of the levels of circulating exosomal miRNAs; i.e., sEV-carried miR-20a-3p is upregulated, and miR-324-5p and miR-186 are downregulated in serum taken from lipodystrophic patients with HIV. These sEVs would target preadipocytes, inducing downregulation of Ltbp2, Nebl, and Wisp2, which would subsequently impair adipocyte differentiation, inflammation, and Lamin C expression. Thus, reduced dicer expression in the adipose among HIV-infected patients may contribute to an altered miRNA signature and adipocyte differentiation and inflammation, which could have potential clinical implications relevant to HIV lipodystrophy. Other tissues affected in HIV lipodystrophy, such as the heart, liver, and muscle, could also be relevant targets of this pathway.