HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes

Abstract

Treatment of human immunodeficiency virus (HIV)-infected patients with HIV protease inhibitors (PIs) has been associated with serious lipid disturbances. However, the incidence and degree of impaired lipid metabolism observed in the clinic vary considerably between individual HIV PIs. Our previous studies demonstrated that HIV PIs differ in their ability to increase the levels of transcriptionally active sterol regulatory element-binding proteins (SREBPs), activate the unfolded protein response (UPR), induce apoptosis, and promote foam cell formation in macrophages. In the present study, we examined the effects of three HIV PIs, including amprenavir, atazanavir, and ritonavir, on the UPR activation and the expression of key genes involved in lipid metabolism in primary rodent hepatocytes. Both atazanavir and ritonavir activated the UPR, induced apoptosis, and increased nuclear SREBP levels, but amprenavir had no significant effect at the same concentrations. In rat primary hepatocytes, cholesterol 7alpha-hydroxylase (CYP7A1) mRNA levels were significantly decreased by atazanavir (38%) and ritonavir (56%) but increased by amprenavir (90%); 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase mRNA levels were increased by amprenavir (23%) but not by ritonavir and atazanavir; low-density lipoprotein receptor mRNA was increased by atazanavir (20%) but not by amprenavir and ritonavir. Similar results were obtained in mouse primary hepatocytes. Atazanavir and ritonavir also decreased CYP7A1 protein levels and bile acid biosynthesis, while amprenavir had no significant effect. The current results may help provide a better understanding of the cellular mechanisms of HIV PI-induced dyslipidemia and also provide useful information to help predict clinical adverse effects in the development of new HIV PIs.

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

“…1B and Dataset S2). This observation is consistent with previous studies reporting the activation of ER-stress-related genes such as GADD34 and CHOP in cells treated with Nelfinavir (20,21,26,27). To get more insight on the type of response engaged by Nelfinavir, we compared this signature with a dataset dissecting the ER-stress response in mouse embryonic fibroblasts (MEFs) (28).…”

Combination Lopinavir and Ritonavir Alter Exogenous and Endogenous Bile Acid Disposition in Sandwich-Cultured Rat Hepatocytes

“…Consistent with this conclusion, 24-h RTV (15-100 mM) exposure reportedly perturbed bile acid synthesis in a concentration-dependent manner by decreasing the activity of cholesterol 7a-hydroxylase, the rate-limiting enzyme in bile acid catabolism (Zhou et al, 2006). Based on these findings, the observed decrease in total measured bile acids after PI exposure in SCRH probably involves regulatory feedback mechanisms that promptly reduce synthesis of bile acids as a protective mechanism.…”

HIV Protease Inhibitors Induce Endoplasmic Reticulum Stress and Disrupt Barrier Integrity in Intestinal Epithelial Cells

“…Our previous studies 1, 10 and others 21 suggest that HIV PI-induced ER stress and activation of the UPR play important roles in HIV PI-associated adverse side effects. To determine whether HIV PIinduced UPR activation in IEC-6 cells is responsible for HIV PI-induced disruption of intestinal barrier integrity, we constructed 3 lentiviral shRNA to knock down the expression of CHOP in IEC-6 cells.…”

“…9 Our previous studies have shown that HIV PIs induce ER stress, activate the UPR, and induce cell apoptosis in both macrophages and hepatocytes. [1][2][3][4]10 Recent studies by Djedaini et al also found that lopinavir (LOPV)-induced ER stress is correlated to insulin resistance in human adipocytes. 11 However, whether HIV PIs also induce ER stress in IECs has not been investigated.…”