Upregulation of scavenger receptor class B type I expression by activation of FXR in hepatocyte.
OBJECTIVE
The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been proposed to play an important role in the pathogenesis of cardiovascular diseases by regulating the metabolism and transport of cholesterol and triglyceride. Scavenger receptor class B type I (SR-BI), a high-density lipoprotein receptor, plays an important role in decreasing lipid metabolism-associated cardiovascular diseases by regulating reverse cholesterol transport. Recent studies have shown that SR-BI expression is upregulated by several nuclear receptors. However, the role of FXR in the regulation of SR-BI expression is not well known. In the present study, we investigate the regulation of SR-BI by FXR in hepatocyte and the corresponding mechanism.


RESULTS
Treatment of human hepatoma cell line HepG2 with FXR ligands resulted in upregulation of SR-BI at the levels of both mRNA and protein. Reporter assays showed that activation of FXR significantly enhanced the SR-BI promoter activity. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that FXR induced SR-BI expression by binding to a novel FXR element (FXRE), a directed repeat DNA motif, DR8 (-703 AGGCCAcgttctagAGCTCA -684). The in vivo experiment demonstrated that gavaging mice with a natural ligand of FXR increased SR-BI expression in liver tissues.


CONCLUSIONS
FXR can directly upregulate SR-BI expression in hepatocyte, and DR8 is a likely novel FXRE that is involved in SR-BI regulation. FXR may serve as a novel molecular target for manipulating SR-BI expression in hepatocyte.
Chao
Fan
F
Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
Gong
Wei
W
Zheng
Yingru
Y
Li
Yuan
Y
Huang
Gang
G
Gao
Min
M
Li
Jialin
J
Kuruba
Ramalinga
R
Gao
Xiang
X
Li
Song
S
He
Fengtian
F
D000818:Animals; D015342:DNA Probes; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
D015342:DNA Probes; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D000099150:Receptor, Farnesoid X-Activated