Indinavir alters sterol and fatty acid homeostatic mechanisms in primary rat hepatocytes by increasing levels of activated sterol regulatory element-binding proteins and decreasing cholesterol 7α-hydroxylase mRNA levels

HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease

“…It has been reported that HIV PIs cause severe hyperlipidemia and lipodystrophy in some patients (Friis-Moller et al, 2003;Hui, 2003;Fontas et al, 2004). Our previous studies showed that indinavir increased the levels of activated SREBP-1 and SREBP-2 in rat hepatocytes (Williams et al, 2004). To examine the effect of HIV PIs on the expression of SREBPs in mouse J774A.1 macrophages, cells were treated with HIV PIs (ritonavir, indinavir, and atazanavir) at therapeutic concentration (15 M) for various times.…”

“…The nuclear extract was isolated from cells as described previously (Williams et al, 2004). The protein concentration was determined using Bio-Rad protein assay reagent.…”

“…Mouse J774A.1 macrophages were plated in DMEM containing 10% FBS for 24 h. Media were replaced with DMEM containing 10% lipoprotein-deficient bovine calf serum. Cells were treated with ritonavir (15 or 25 M) or control vehicle for 24 h in the presence (20 g/ml) or absence of LDL and pulsed with [ 3 H]oleate (2 Ci/ml) for 2 h. The lipids were extracted with hexane/isopropyl alcohol [3:2 (v/v)] as described previously (Williams et al, 2004 …”

“…Moreover, HAART significantly increases the risk of premature atherosclerosis and myocardial infarction (Holmberg et al, 2004). Recent studies suggest that PIs disrupt cellular lipid homeostasis by increasing the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs) (Riddle et al, 2001;Williams et al, 2004), endoplasmic reticulum (ER) membrane-bound transcription factors that when proteolytically activated increase the expression of dozens of genes involved in lipid metabolism (Horton et al, 2002). However, the cellular/molecular mechanisms underlying the HIV PIassociated metabolic abnormalities remain elusive and maybe multifactorial.…”

Transcriptional Regulation of Metabolism

“…25). Alternatively, it has been suggested that protease inhibitors might affect the SREBP maturation process, resulting in impaired nuclear accumulation of SREBP-1 (27,317). A better understanding of the molecular mechanisms at work would clearly be extremely helpful for designing the best therapeutic strategy.…”