FIGURE 1.

Activation of hepatic FXR increases SR-BI expression and specifically lowers plasma HDL-C. A and B, wild-type (WT) mice were gavaged with either vehicle or GW4064 for 7 days (n = 5 mice per group). After a 6-h fast, blood was collected. Plasma lipoprotein/cholesterol profile was determined by FPLC (A) and hepatic mRNA levels of genes involved in lipid metabolism determined by qRT-PCR (B). C, liver-specific Fxr^−/− (ΔL) mice and their wild-type littermates (F/F) were gavaged with either vehicle or GW4064 as described under “Experimental Procedures.” Hepatic mRNA levels were quantified by qRT-PCR (n = 4–5 mice per group). D, Western blot assays were performed to determine hepatic protein levels of wild-type mice treated with either vehicle or GW4064 for 7 days (top panel) or infected with Ad-VP16 (VP16) or Ad-Fxrα2-VP16 (Fxrα2) for 7 days (lower panel). LDLR, low density lipoprotein receptor; LRP, LDL receptor-related protein; CYP8B1, sterol 12-α-hydroxylase; HMGCS, HMG-CoA synthase; HMGCR, HMG-CoA reductase; ACAT, acyl-coenzyme A:cholesterol acyltransferase; VLDL, very low density lipoprotein; LDL, low density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; ABCG5, ATP-binding cassette subfamily G member 5. *, p < 0.05; **, p < 0.01; #, p < 0.001 versus vehicle treatment.