-The HIV protease inhibitor indinavir blocks the differentiation of fat cell precursors into mature cells by interfering with the activity of a crucial regulatory protein, researchers in France say.
"Protease inhibitors used in the treatment of HIV infection have been causally associated with lipodystrophy and insulin resistance and were shown to alter adipocyte differentiation in cultured cells," explained Martine Caron and colleagues at St. Antoine Medical University in Paris. "We aimed to delineate the mechanism by which indinavir impaired adipocyte function."
Caron and coworkers found that indinavir disrupted the nuclear localization of sterol regulatory element-binding protein-1 (SREBP-1), which effectively short-circuited the process of preadipocyte differentiation.
SREBP-1 levels in indinavir-treated patients were markedly lower than normal, as were levels of peroxisome proliferator-activated receptor (gamma) (PPAR-(gamma)) and insulin receptor (IR). These patients also displayed pronounced reductions in the number of new adipocytes, with adipocyte conversion depressed by up to 60%, the researchers said.
The researchers discovered alterations in the electrophoretic mobility of SREBP-1, which, combined with lowered SREBP-1 immunoreactivity in the nuclei of indinavir-exposed cells, resulted in an accumulation of the protein outside the nuclei it was now unable to successfully enter. These accumulations were correlated with incomplete adipocyte differentiation observed in indinavir-treated patients.
While indinavir did not affect preadipocyte growth or overall insulin sensitivity, it did produce a specific resistance to insulin activation of mitogen-activated protein kinase at some point before or after tyrosine phosphorylation of IR substrate-1 ("The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance," Diabetes, June 2001;50(6):1378-1388).
Caron and colleagues concluded that "indinavir impairs differentiation at an early step of adipose conversion probably involving the process controlling SREBP-1 intranuclear localization."
The corresponding author for this report is Martine Caron, Institut National de la Sante et de la Recherche Medicale (INSERM) U 402, Faculte de Medecine Saint-Antoine, 27 Rue Chaligny, F-75571 Paris 12, France.
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Key points reported in this study include
- The HIV protease inhibitor indinavir blocks the differentiation of fat cell precursors into mature cells by interfering with the activity of a crucial regulatory protein
- This protein, sterol regulatory element-binding protein-1 (SREBP-1), was present at reduced levels in indinavir-treated patients
- The effects of indinavir disrupted SREBP-1 intranuclear localization, resulting in impaired adipocyte differentiation
This article was prepared by AIDS Weekly editors from staff and other reports.