Study On Transcriptional Regulation Mechanism Of FXR On RECK And The Role Of FXR In

Part â…  Farnesoid X receptor activates transcription of RECK through FXR response element in the1st intronFarnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. It is highly expressed in the liver, intestine, kidney, and adrenals, but with lower expression in fat and heart. As a transcription factor, FXR regulates the expression of a wide variety of target genes by binding either as a monomer or as a heterodimer with RXR to FXR response elements (FXREs). FXR plays key roles in bile acid, cholesterol, lipid, and glucose metabolism. Besids, FXR may protect the liver from chronic hepatic injury such as liver fibrosis.RECK (reversion-inducing cysteine rich protein with Kazal motifs), a newly discovered membrane-anchored protein, significantly inhibit matrix metalloproteinases (MMP) involved in breakdown of the extracellular matrix (ECM). Besides tumor invasion and metastasis, MMP and their inhibitors (TIMP) contribute to the progression and regression of liver fibrosis.Here we find that activated FXR can positively regulates the expression of RECK in vivo and in vitro. Luciferase reporter gene assays and Chromatin Immunoprecipitation data support that FXR directly controls RECK transcription via IR1-type element identified in the first introns of the human, mouse and rat RECK genes. The inhibition of MMP activity in mouse NAFLD models may be partly mediated via increased RECK expression by FXR agonist. Part â…¡ The role of Farnesoid X receptor in hepatocellular carcinomaLiver cancer is one of the most common forms of cancer, ranking the highest morbidity and mortality worldwide. Hepatocellular carcinoma (HCC) is the primary liver tumor that accounts for more than90%of all liver tumors in China. The development of cancer is a multi-step process, and the exact mechanism of hepatocarcinogenesis remains unknown. Nuclear receptors comprise a family of transcription factors that regulate gene expression in a ligand dependent manner. They can activate or repress target genes involved in key physiological and pathological processes. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily. Predominantly expressed in liver and kidney, FXR controls bile acid and lipid homeostasis. FXR deficiency mice spontaneously develop HCC and show an increased prevalence for intestinal malignancies, suggesting a role of FXR as a tumor suppressor in enterohepatic tissues. Here we found that FXR expression and activity was lower in HCC tissues. Through the induction of tumor suppressor gene p18and RECK, FXR agonist could inhibit cell viability and induce cell apoptosis in hepatoma cells. Thus, FXR agonists may show a potential in the prevention and/or treatment of human hepatocellular carcinoma, a devastating malignancy with increasing prevalence and limited therapeutic options.