Upregulation of Scavenger Receptor BI by Hepatic Nuclear Factor 4αthrough a Peroxisome Proliferator-Activated Receptorγ-Dependent Mechanism in Liver

Hepatic nuclear factor 4 α (HNF4 α ) modulates the transcriptional activation of numerous metabolic genes in liver. In this study, gene-array analysis revealed that HNF4 α overexpression increased peroxisome proliferator-activated receptor γ (PPAR γ ) greatly in cultured rat primary hepatocytes. PPAR-response-element-driven reporter gene expression could be elevated by HNF4 α . Bioinformatics analysis revealed a high-affinity HNF4 α binding site in the human PPAR γ 2 promoter and in vitro experiments showed that this promoter could be transactivated by HNF4 α . The presence of HNF4 α on the promoter was then confirmed by ChIP assay. In vivo , hepatic overexpression of HNF4 α decreased cholesterol levels both in plasma and liver and several hepatic genes related to cholesterol metabolism, including scavenger receptor BI (SR-BI), were upregulated. The upregulation of SR-BI by HNF4 α could be inhibited by a PPAR γ antagonist in vitro . In conclusion, HNF4 α regulates cholesterol metabolism in rat by modulating the expression of SR-BI in the liver, in which the upregulation of PPAR γ was involved.