Background:  HAART with some protease inhibitors (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) is associated with hyperlipidemia. In contrast to a PI, the NNRTI efavirenz (EFV) increases both total and high density cholesterols, which may mitigate atherogenic effects. EFV inhibits the lipogenic pathway in murine adipocytes in vitro, but the effect on human adipocytes and hepatocytes is unknown.

Methods:  Lipogenesis was assayed as [¹⁴C]2-acetate incorporation into triglycerides and cholesterol in fully differentiated human primary adipocytes and HepG2 hepatoma cells. Lipolysis was assessed as glycerol release (± isoproterenol stimulation) and insulin-stimulated glucose uptake was determined using [³H]deoxyglucose. The activation of the lipogenic transcriptional factor sterol regulatory element binding protein (SREBP) was measured in HepG2 cells using transient transfection with a response element linked to a luciferase reporter gene.

Results:  At concentrations up to 30 µM, EFV was not cytotoxic, as measured by cell adenosine triphosphate or protein content, but inhibited triglyceride and cholesterol synthesis in a concentration and time-dependent manner in both hepatocytes and adipocytes, and blunted activity of SREBP (see the table). The lowest inhibitory concentration was 5 µM (EFV C_max ~5 to 12 µM). Cholesterol synthesis was inhibited at lower concentrations than triglyceride synthesis after 16 hours and 5 days. The IC₅₀ for inhibition of SREBP2 was 10.4 µM after a 16-hour incubation. EFV did not affect adipocyte glucose uptake or promote lipolysis (± isoproterenol stimulation).

	IC50 (µM) 16 Hours		IC50 (µM) 5 Days
	Triglyceride	Cholesterol	Triglyceride	Cholesterol
HepG2	31.9	15.3	7.3	5.9
Adipocytes	> 30	16.8	> 30	29.1

Keywords: efavirenz; dyslipidemia; lipodystrophy