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 , Ppar γ, C/ebpa , Fasn , adiponectin , Glut4 , CD36 ), and Lamin C , and increased expression of genes involved in inflammation ( IL1 β , 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.

miRNA Expression Profiling in Subcutaneous Adipose Tissue of Monozygotic Twins Discordant for HIV Infection: Validation of Differentially Expressed miRNA and Bioinformatic Analysis

“…A potential role of miRNAs has been postulated also in the onset of HALS. Mice knock-out (KO) for Dicer, a ribonuclease involved in miRNA biogenesis, display a form of lipodystrophy reminiscent of the human HALS, including the loss of subcutaneous (SC) fat, insulin resistance, and dyslipidemia [ 14 ]. Dicer mRNA expression appears also downregulated in SC fat depots (i.e., dorsocervical and abdominal) of HIV + patients [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], suggesting that its reduced expression could lead to a broad altered expression profile of several cellular miRNAs [ 25 ].…”

“…Mice knock-out (KO) for Dicer, a ribonuclease involved in miRNA biogenesis, display a form of lipodystrophy reminiscent of the human HALS, including the loss of subcutaneous (SC) fat, insulin resistance, and dyslipidemia [ 14 ]. Dicer mRNA expression appears also downregulated in SC fat depots (i.e., dorsocervical and abdominal) of HIV + patients [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ], suggesting that its reduced expression could lead to a broad altered expression profile of several cellular miRNAs [ 25 ]. Accordingly, in samples of SC adipose tissue of lipodystrophic HIV + patients, the upregulation of specific miRNAs, which controls the expression of genes involved in adipocyte differentiation and apoptosis was observed [ 15 ].…”

“…In particular, in HIV lipodystrophy patients it has shown an altered pattern of circulating miRNAs [ 14 ]. Given the emerging relevance of miRNAs in several pathological conditions, we investigated miRNA expression profiles in SC and plasma samples of two subjects.…”

Omega-3/Omega-6 Long-Chain Fatty Acid Imbalance in Phase I Retinopathy of Prematurity

“…Sequencing of the libraries was conducted at the HMS Biopolymer Facility using an Agilent 4200 Tapestation instrument as previously described [ 40 ]. A corresponding Agilent High Sensitivity D1000 ScreenTape assay was used to visualize the libraries and check that the size and concentrations of the libraries matched the expected product.…”

Molecular and Cellular Bases of Lipodystrophy Syndromes

“…To note, HIV-related lipodystrophies which are reviewed elsewhere ( 4 ), also result from altered adipocyte differentiation and inflammatory dysregulation ( 123 ).…”