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Background:  Dyslipidemia has been associated with use of several HIV PI. In contrast, HIV treatment with atazanavir (ATV) results in antiviral efficacy with favorable lipid profiles. Several PI inhibit proteasome activity in vitro at therapeutic levels, while ATV inhibits only at levels exceeding Cmax. We propose that ATV’s favorable lipid profile and reduced proteasome effects are mechanistically linked.

Methods:  HepG2 and differentiated 3T3-L1 cells were treated for 24 hours with PI (3-30 mM). Transcription profiles used Affymetrix chips (triplicates, compared by t-test) verified by qPCR. Lipid synthesis was assayed by ¹⁴C-acetate incorporation. Sterol-regulatory element binding protein (SREBP) was assayed by Western blot of nuclear extracts and SRE-promoter/luciferase-reporter assay.

Results:  A pattern of induction previously linked to proteasome inhibition, ER stress, and the unfolded protein response (UPR) was seen with ritonavir (RTV) and nelfinavir (NFV) in HepG2 cells, while ATV affected fewer genes and at lower magnitudes. Among induced genes were transcription factors (e.g. ATF-4) and enzymes of amino acid and glutathione metabolism, and moderate increases in lipogenic enzymes (examples in the table). This profile correlated with elevated triglyceride and cholesterol biosynthesis (2-to 3-fold with RTV and NFV, no change with ATV) and nuclear SREBP-1c protein levels in HepG2 cells, and increased SRE-promoter activity in a transfected cell line (HEK-293), consistent with hepatic lipid overproduction. The adipocyte transcription profile also revealed the UPR, but lipid synthesis rates and lipogenic enzyme expression were suppressed by RTV, NFV, lopinavir, and moderately by ATV, consistent with suppression of fat storage by adipocytes.