9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 19-21 July 2007, Sydney, Australia

MOLECULAR MECHANISM FOR EFAVIRENZ EFFECTS ON LIPID METABOLISM

Antiviral Therapy 2007; 12(Suppl. 2):L6 (abstract no. O-03B)

O Flint, A Bellamine, M Noor and R Parker
Research and Development, Bristol-Myers Squibb Co, Princeton, NJ, USA

BACKGROUND: Efavirenz (EFV) therapy is associated with elevated HDL-cholesterol (HDL-C). Cholesterol ester transfer protein (CETP) is secreted from liver and adipose tissue and regulates HDL levels by mediating cholesterol ester exchange among lipoproteins. EFV is not a direct inhibitor of CETP activity, but decreases expression of some lipogenic genes in vitro. We identified CETP as an additional EFV-suppressed gene, and proposed that decreased liver X receptor (LXR) activity could explain the gene regulation pattern.

METHODS: LXR activity was measured by cell-based LXR- Gal4/luciferase and SRE-promoter-Luc reporter transactivation in HEK293 or hepatoma lines with T-0901317 or 24,25-epoxycholesterol (synthetic and natural LXR agonists), and a ligand-binding assay using recombinant LXR-α and -β. Lipid synthesis was assayed in HepG2 and 3T3-L1 cells along with mRNA for CETP and other LXR target genes by RT-PCR.

RESULTS: In hepatoma and 3T3-L1 cells, EFV (1–10 µM, 6–48 h) reduced mRNA for the LXR target genes CETP (60%), SREBP1c (90%), and FAS (50% at 10 µM) at 10 µM, but not LXR itself. LXR agonist-induced lipid synthesis and gene expression in HepG2 cells were blocked by EFV (1–10 µM) with effects dependent on agonist concentration. In transactivation assays, EFV (EC₅₀ ~7 µM) antagonized effects of the synthetic and natural agonists, and in binding assays, EFV directly displaced 3H-24,25-epoxycholesterol from purified LXR-α and -β (EC₅₀ ~11 µM).

CONCLUSIONS: At levels approaching its C_max, EFV antagonizes LXR transcriptional activity in cells and displaces binding of natural and synthetic LXR agonists in vitro. These effects provide a possible mechanism for EFV suppression of lipogenic gene expression including the important LXR target gene CETP in liver and adipose cell lines. These findings support a hypothesis for EFV-mediated elevation of HDL-C through LXR antagonism and reduction in CETP expression and activity.

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2007-07-24
O-03B

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