Effects of the HIV-1 protease inhibitor ritonavir on preadipocyte differentiation.

Abstract

HIV-1 protease inhibitor therapy is associated with a novel lipodystrophy syndrome characterized by truncal adiposity, peripheral fat atrophy, dyslipidemia, and type 2 diabetes. The increase in truncal fat may be due to increase in adipocyte number as a result of enhanced preadipocyte differentiation. We show that addition of 10 mug/ml ritonavir to standard differentiation medium enhanced 3T3-L1 preadipocyte differentiation as measured by a 30% increase in triacylglycerol (TG) accumulation and a 50% increase in glycerol 3-phosphate dehydrogenase (GPDH) activity. Although ritonavir partially inhibited protein expression of peroxisome proliferator activated receptor gamma (PPARgamma), CCAAT/enhancer binding protein alpha (C/EBPalpha), and the aP2 gene (which encodes the adipocyte lipid binding protein), it resulted in higher levels of the active form of adipocyte determination and differentiation-dependent factor-1 (ADD-1), also known as sterol regulatory element binding protein 1 (SREBP-1). The enhancing effects of ritonavir on late events of 3T3-L1 preadipocyte differentiation may be mediated by ADD-1/SREBP-1 which has been shown to directly activate transcription of several genes encoding lipogenic enzymes. Preliminary results suggest that ritonavir preferentially enhances differentiation of human preadipocytes derived from abdominal omental but not subcutaneous adipose tissue in primary culture.