Figure 7.

Model for PGC-1α to activate FXR and regulate triglyceride metabolism. PGC-1α, PPARγ, and HNF4α mRNAs are induced after a prolonged fast. PGC-1α coactivates PPARγ and/or HNF4α bound to a DR-1 element in the FXR promoter, to induce FXR mRNA expression. In addition, PGC-1α interacts directly with FXR to enhance transcription of FXR target genes. Activation of FXR target genes by PGC-1α and FXR results in a decrease in SREBP-1c expression and in increased expression of genes involved in triglyceride metabolism and clearance. On the other hand, PGC-1α may also repress SREBP-1c expression in an FXR-independent manner. The decrease in SREBP-1c expression may reduce triglyceride synthesis/secretion and lower plasma triglyceride levels. The decrease in triglyceride synthesis in the liver may reduce storage of fatty acids and increase fatty acid β-oxidation to meet the normal energy demands during fasting.