It has been reported that the major function of the sterol regulatory element binding protein 2 (SREBP-2) is to activate preferentially cholesterol biosynthesis in liver and adipose tissue rather than fatty acid synthesis. In the current study, we analyzed the effects of overexpression of human dominant-positive SREBP-2 transgene under control of PEPCK promoter in the spontaneously hypertensive rat (SHR) on lipid and glucose metabolism. Transgenic overexpression of SREBP-2 was associated with significantly higher hepatic triglycerides (20.4+/-0.9 vs. 17.0+/-0.05 micromol/g, P<0.05) but not cholesterol (10.6+/-0.4 vs. 10.9+/-0.4 micromol/g) and decreased relative weight of epididymal fat pad (0.73+/-0.03 vs. 0.83+/-0.03, P<0.05). In addition, muscle triglyceride (15.8+/-3.7 vs. 8.5+/-1.2 micromol/g, P<0.001) and cholesterol (3.6+/-0.5 vs. 2.1+/-0.1 micromol/g, P<0.05) concentrations were significantly increased in transgenic rats when compared to SHR controls. Ectopic fat accumulation was associated with significantly increased serum glucose levels (6.4+/-0.1 vs. 5.9+/-0.1 mmol/l, P<0.005) and reduced insulin levels (1.78+/-0.33 vs. 2.73+/-0.37 nmol/l, P<0.05) in transgenic rats. These results provide evidence for important role of SREBP-2 in regulation of lipid and glucose metabolism.