OBJECTIVE To study the effect of Daxx on cholesterol accumulation in hepatic cells. METHODS Sprague Dawley (SD) rats were fed a normal or high fat diet for 6 wk, and serum lipids and Daxx expression of hepatic tissues were measured by immunoblot assays. HepG(2) cells were transfected with the pEGFP-C1/Daxx or pEGFP-C1 plasmid. Cells stably transfected with Daxx were identified by RT-PCR analysis. Total cholesterol levels were determined by high performance liquid chromatography. Activated-SREBP and caveolin-1 were assayed by western blotting. RESULTS Hepatic Daxx protein was higher in normal rats than in high fat diet-fed rats. Noticeable negative correlations were seen between Daxx and LDL-C (gamma = -7.56, P = 0.018), and between Daxx and TC (gamma = -9.07, P = 0.01), respectively. The total cholesterol of HepG(2)/GFP-Daxx cells was lower than that of control cells or HepG(2)/GFP cells (9.28 +/- 0.19 vs 14.36 +/- 4.45 or 13.94 +/- 2.62, both P < 0.05). Furthermore, in HepG(2)/GFP cells, the expression of activated SREBP was lower than that of control cells, whereas caveolin-1 expression was higher. CONCLUSIONS Overexpression of Daxx in HepG(2) cells decreased intracellular cholesterol accumulation, which might be associated with inhibition of SREBP activity and an increase in caveolin-1 expression.