Abstract
Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).
Highlights
Lipodystrophy is the most common adverse event in human immunodeficiency virus (HIV)-infected individuals receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART), and more than half of the patients receiving HAART/ART develop HIV-associated lipodystrophy [1,2,3,4]
We previously reported that adipose tissue-derived stem cells (ADSCs) from HIV-infected patients exhibit indistinguishable physiological properties and potentials for adipocyte differentiation in vitro [25], which enabled us to examine whether detrimental effects of protease inhibitor (PI) could have occurred on differentiating human adipocytes
ADSCs are able to differentiate to adipocytes in special medium promoting adipogenic differentiation
Summary
Lipodystrophy is the most common adverse event in human immunodeficiency virus (HIV)-infected individuals receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART), and more than half of the patients receiving HAART/ART develop HIV-associated lipodystrophy [1,2,3,4]. One of the two major families of medicine, nucleoside reverse transcriptase inhibitor (NRTI), was reported to cause lipodystrophy through its effects on mitochondria, which results in apoptosis induction in adipocytes [4,9,10,11,12] Another family, protease inhibitor (PI), was found to be associated with lipodystrophy [4,13,14,15]. Examinations of the effects of PIs on adipose tissue-derived stem cells (ADSCs) are critical, as ADSCbased regenerative medicine could be a promising remedy for lipodystrophy. It is indispensable for the development of improved HAART/ART for HIV-infected patients. The cells of origin in ATV-induced lipodystrophy are not ADSCs, but adipocytes undergoing differentiation, suggesting that protease(s) associated with adipogenesis are the possible target(s) responsible for ATV-induced ER stress
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