Activation of the farnesoid-X-nuclear receptor (FXR) induces the transcription of numerous genes that affect the regulation of multiple metabolic pathways. The importance of FXR in normal physiology can be seen in animals where dysregulation of FXR has been shown to be associated with abnormal bile acid metabolism, hyperlipidemia, atherosclerosis, hyperglycemia, increased susceptibility to hepatotoxins, hepatocarcinoma and increased permeability of the intestinal barrier. Despite this plethora of effects, the central role of FXR in regulating virtually all aspects of bile acid metabolism and th enterohepatic circulation is particularly important. The hepatic synthesis of chenodeoxycholic acid (CDCA) and cholic acid (CA) is regulated by the enzymes Cyp7a1 and Cyp8b1, respectively. Numerous studies have supported a model in which activation of hepatic and intestinal FXR results in repression of Cyp7a1 and/or Cyp8b1. Current dogma suggests that repression of these two genes is dependent upon increased levels of SHP in the liver and/or the interaction of intestinally- derived Fgf15/19 with its cognate receptor on the hepatocyte plasma membrane. However, the relative importance of SHP and Fgf15/19, and the mechanisms involved in acute or long-term repression of Cyp7a1 and Cyp8b1 remains to be established. Indeed, the current data suggest that additional as yet unknown, pathways may also be involved in repression of these two genes. Herein, we identify two novel pathways that are involved in the repression of Cyp7a1 and Cyp8b1. First, we identified two transcriptional repressors as novel FXR target genes. Neither gene was known to be involved in bile acid or lipid metabolism. We then used gain-of-function and loss-of-function studies to demonstrate that these repressors function to repress Cyp8b1 and Cyp7a1, respectively. Importantly, such repression altered the ratios of specific bile acids in the bile acid pool. In addition, we demonstrate the regulation of number of glutathione transferases, and related genes, that function to protect the liver from toxic challenges. Together, these preliminary studies i) challenge the current paradigm that SHP and Fgf15/19 are the major/sole regulators of Cyp7a1 and Cyp8b1 and ii) provide a mechanism that explains the hepato-protection that can result from FXR activation. The proposed experiments will extend these novel findings and identify the molecular mechanisms involved. A better understanding of the effects of FXR activation appears particularly important, as FXR agonists are currently being tested in clinical trials.
Recent data from genome wide association studies (GWAS) identified various signaling pathways that are associated with Cardiovascular Disease (CAD); these pathways included atherosclerosis (including cholesterol), inflammation and the nuclear receptors FXR and LXR. The current proposal involves studies on two novel FXR target genes that regulate catabolism of cholesterol to bile acids, inflammation and resistance to hepatic toxins. A better understanding of these two genes, that likely affect CAD and liver disease, may provide novel pharmacological targets leading to improved treatments.
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