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The Effects of Farnesoid X Receptor on Fibroblast Growth Factor 21 and the Mechanism

Author: WangYongChao
Tutor: JiangYu
School: Third Military Medical University
Course: Biochemistry and Molecular Biology
Keywords: Farnesyl ester alcohol X receptor Fibroblast growth factor 21 Obesity
CLC: R363
Type: Master's thesis
Year: 2011
Downloads: 30
Quote: 0
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Abstract


Background: Obesity is increasingly becoming an important factor for harm to human health, often accompanied by high cholesterol, high blood pressure, high cholesterol and diabetes. Fibroblast growth factor 21 (Fibroblast growth factor 21, FGF21) is a newly discovered metabolic regulation factor, a large number of experimental studies have shown that FGF21 has an important regulatory function in glucose and lipid metabolism, resistant to diet-induced obesity, obese animals weight significantly reduced. As one of the members of the nuclear receptor superfamily, farnesoid X receptor (farnesoid X receptor FXR), by regulating the expression of many target genes in the regulation of glucose metabolism, lipid metabolism and cholesterol metabolism plays an extremely important role in but FXR FGF21 expression has been reported. Both are highly expressed in the liver, and play an important role in glucose and lipid metabolism, we speculate that FGF21 is a target gene of FXR?'ll Understand FXR and FGF21 biological function and mechanism, and provide prevention and treatment of obesity important scientific basis, and to provide new potential therapeutic targets. Objective: To explore the FXR activation is able to regulate the expression of FGF21 and its regulation mechanisms preliminary study. Methods: In this study, were given the human hepatoma cell line HepG2 and human fetal liver cell line L02 FXR of different concentrations agonists CDCA or GW4064 treatment 24 hours, using reverse transcriptase-polymerase chain reaction (RT-PCR) method, the Realtime PCR method and by Western Blot detection changes in FGF21mRNA and protein expression; 2 online prediction FXR in the FGF21 gene promoter 5 'flanking promoter region of possible binding sites, ER10 highest score, FXR binding sites most likely; extract HepG2 cell genomic DNA, using the PCR method contains the ER10 sites FGF21 gene promoter region was amplified construct the luciferase reporter gene plasmid pGL 3 (-1790 / 111), while building does not contain ER10 sites the pGL 3 (-768 / 111), the use of liposomes, the activity of FXR expression plasmid VP-FXR respectively with the two recombinant plasmids were co-transfected contingent to HepG2 cells after 24 hours to detect the reporter gene activity. 3 18 C57BL / 6 mice were randomly divided into three groups, according to the body weight of mice three groups of mice were given different amounts of CDCA (0.1% DMSO, 10mg/kg, 50mg/kg) for 7 days were killed, the liver by RT-PCR and Western-blot were used to detect the mouse liver FGF21mRNA and protein expression. Results: 1.FXR activation significantly raised two liver cells FGF21mRNA and protein expression levels in a dose-dependent; 2 luciferase reporter gene recombinant vector PGL 3 (-1790 / 111) and PGL of 3 (-768 / 111), respectively, and VP-FXR transfected into HepG2 cells, pGL 3 (-1790 / 111) activity was significantly increase, while the PGL 3 (-768 / 111) active no significant changes. Can 3.CDCA be significantly up-regulated the expression of of FGF21 molecules of mRNA and protein in C57BL / 6 mouse liver and in a dose-dependent. Conclusion: The above experimental results prove that FXR activation in cultured hepatocytes and mice to increase the expression of FGF21, FXR increases the FGF21 expression of molecular mechanisms may be achieved through a combination of FGF21 gene promoter ER10 sequence may ER10 FXR binding sites, FXR FGF21 regulation mechanisms need to be further clarified. These studies to clarify the role of FXR and FGF21 in obese and provide an important scientific basis for effective prevention and treatment of obesity, and could be a potentially important target for clinical treatment of obesity.

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