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.
Highlights
HIV lipodystrophy is the most prevalent form of acquired lipodystrophy [1]
These dorsocervical adipose tissue measurements obtained by imaging confirmed our clinical assessment for lipodystrophy in which participants with lipodystrophy were recruited for presence of increased dorsocervical fullness (Table 1)
The HIV population frequently presents with a redistribution of fat and metabolic abnormalities, including dorsocervical adipose lipohypertrophy, ectopic fat accumulation, subcutaneous adipose dysfunction, insulin resistance, and dyslipidemia
Summary
HIV lipodystrophy is the most prevalent form of acquired lipodystrophy [1]. The altered fat distribution seen in HIV lipodystrophy has significant implications for metabolic risk, including cardiovascular disease [2, 3] and nonalcoholic fatty liver disease [4], which are leading contributors to morbidity and mortality in HIV. Individuals with HIV lipodystrophy can present with lipohypertrophy, with increased fat in the abdomen, viscera, and dorsocervical areas, and/or lipoatrophy, with loss of fat in the face, extremities, and subcutaneous depots. These changes are usually associated with insulin resistance, metabolic dysregulation, and inflammation. Recent progress by our group has focused on a mechanistic hypothesis for adipose dysfunction and metabolic changes in HIV, relating to the dysregulation of Dicer [6], an integral protein in the microRNA (miRNA) processing pathway, and its subsequent effects on critical miRNAs regulating adipogenic pathways [7, 8]
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