The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance

Protease inhibitors used in the treatment of HIV infection have been causal ly associated with lipodystrophy and insulin resistance and mere shown to a lter adipocyte differentiation in cultured cells. We aimed to delineate the mechanism by which indinavir impaired adipocyte function. We report that i ndinavir altered neither the growth nor insulin sensitivity of 3T3-F442A pr eadipocytes, nor did it alter the initial step of their differentiation, i. e., clonal proliferation. However, adipose conversion was inhibited by indi navir (by 50-60%), as shown by 1) the decrease in the number of newly forme d adipocytes; 2) the lower level of the adipogenic protein markers, sterol regulatory element-binding protein-1 (SREBP-1), peroxisome proliferator-act ivated receptor-gamma (PPAR-gamma), and the insulin receptor (IR); and 3) t he lack of SREBP-1 and PPAR-gamma immunoreactivity in the nucleus of most i ndinavir-treated cells. Partial adipose conversion also correlated with an accumulation of SREBP-1 at the nuclear periphery and an alteration in its e lectrophoretic mobility. Defective expression and nuclear localization of P PAR-gamma probably resulted from the decreased level of nuclear SREBP-1. In dinavir also rendered 3T3-F442A adipocytes resistant to insulin for mitogen -activated protein kinase activation ata step distal to IR substrate-1 tyro sine phosphorylation. Hence, indinavir impairs differentiation at an early step of adipose conversion probably involving the process controlling SREBP -1 intranuclear localization.