Antiretroviral-Related Adipocyte Dysfunction and Lipodystrophy in HIV-Infected Patients: Alteration of the PPARγ-Dependent Pathways

Lipodystrophy and metabolic alterations are major complications of antiretroviral therapy in HIV-infected patients. In vitro studies using cultured murine and human adipocytes revealed that some protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were implicated to a different extent in adipose cell dysfunction and that a chronic incubation with some PIs decreased mRNA and protein expression of PPAR gamma. Defective lamin A maturation linked to PI inhibitory activity could impede the nuclear translocation of SREBP1c, therefore, reducing PPAR gamma expression. Adipose cell function was partially restored by the PPAR gamma agonists, thiazolidinediones. Adverse effects of PIs and NRTIs have also been reported in macrophages, a cell type that coexists with, and modulates, adipocyte function in fat tissue. In HIV-infected patients under ART, a decreased expression of PPAR gamma and of PPAR gamma-related genes was observed in adipose tissue, these anomalies being more severe in patients with ART-induced lipoatrophy. Altered PPAR gamma expression was reversed in patients stopping PIs. Treatment of patients with agonists of PPAR gamma could improve, at least partially, the subcutaneous lipoatrophy. These data indicate that decreased PPAR gamma expression and PPAR gamma-related function, resulting from ART-induced adipose tissue toxicity, play a central role in HIV-related lipoatrophy and metabolic consequences. Copyright (C) 2009 Martine Caron et al.