Bile acids have been implicated in the development of colorectal cancers. We investigated the expression of the transcription factor regulated by bile acids, farnesoid X receptor (FXR), as well as other components of this pathway in human colorectal tumors and cell lines. The most significant changes were a decrease in FXR mRNA levels in adenomas (5-fold average) and carcinomas (10 fold average) and an increase in peroxisome proliferator activated receptor-gamma (2-fold average). FXR was not expressed in undifferentiated colon adenocarcinoma SW480 cells and metastasis derived SW620 cells. In Caco-2 and HT-29 cells, the level of FXR expression increased with the degree of differentiation. Intestinal bile acid binding protein was activated by chenodeoxycholic acid and the synthetic FXR agonist GW4064 in Caco-2 and HT-29 but not in SW cells unless FXR was transfected. The down-regulation of the nuclear receptor FXR in colon cancer might be of clinical and pharmacological importance.

In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.

The orphan nuclear receptors FXR and LXRalpha have become challenging targets for the discovery of new therapeutic agents. Bile acids and hydroxysterol intermediates are the respective natural ligands of these two structurally and functionally closely related receptors. Both FXR and LXRalpha; are thought to play a major role in the control of cholesterol catabolism by regulating the expression of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of bile acid synthesis. Reverse cholesterol transport might also be affected by FXR and LXR since they control the expression of PLTP and CETP, two proteins involved in the transfer of phospholipid, cholesterol and cholesteryl esters among plasma lipoproteins. A new class of potent synthetic activators of FXR, the 1,1-bisphosphonate esters, has been discovered which up regulate the Intestinal Bile Acid Binding Protein gene (I-BABP) as demonstrated for chenodeoxycholic acid, however there are no known synthetic activators yet identified for LXRalpha. The evaluation of FXR as a potential target for the development of drugs affecting plasma cholesterol can take advantage of the fact that the activators of FXR (farnesol, bile acids and the 1,1-bisphosphonate esters) have been studied in various in vitro and in vivo models. Administration of chenodeoxycholic acid to animals and man did not result in the increase in plasma cholesterol expected from a decrease in cholesterol 7alpha-hydroxylase expression. Like farnesol, the 1,1-bisphosphonate esters increase the rate of degradation of HMGCoA reductase and have the unexpected property of inducing hypocholesterolemia in normal animals. The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.

The unique steroidogenic and hypertensive side effects of torcetrapib may be linked and involve voltage-gated L-type Ca channels. Structurally unrelated cholesteryl ester transfer protein inhibitors such as dalcetrapib do not share this effect.

To our knowledge, this is the first nutrition screening tool designed for staff RNs that has been tested for both validity and reproducibility.