HIV protease inhibitors stimulate hepatic triglyceride synthesis

Hyperlipidemia may complicate the use of HIV protease inhibitors (PIs) in A IDS therapy. To determine the cause of hyperlipidemia, the effect of PIs on lipid metabolism was examined with HepG2 liver cells and AKR/J mice. In He pG2 cells, the PIs ABT-378, nelfinavir, ritonavir, and saquinavir stimulate d triglyceride synthesis; ritonavir increased cholesterol synthesis; and am prenavir and indinavir had no effect. Moreover, nelfinavir increased mRNA e xpression of diacylglycerol acyltransferase and fatty acid synthase. The re tinoid X receptor agonist LG100268, but not the antagonist LG100754, furthe r increased PI-stimulated triglyceride synthesis and mRNA expression of fat ty acid synthase in vitro. In fed mice, nelfinavir or ritonavir did not aff ect serum glucose and cholesterol, whereas triglyceride and fatty acids inc reased 57% to 108%. In fasted mice, ritonavir increased serum glucose by 29 %, cholesterol by 40%, and triglyceride by 99%, whereas nelfinavir had no e ffect, suggesting these PIs have different effects on metabolism. Consisten t with the in vitro results, nelfinavir and ritonavir increased triglycerid e 2- to 3-fold in fasted mice injected with Triton WR-1339, an inhibitor of triglyceride clearance. We propose that PI associated hyperlipidemia is du e to increased hepatic triglyceride synthesis and suggest that retinoids or meal restriction influences the effects of select PIs on lipid metabolism.