The end products of cholesterol utilization are the bile acids
Achlorhydria the absence of hydrochloric acid in gastric juice
Bile acid synthesis represents the major pathway for the elimination of excess cholesterol from the body (, ; ). Bile acids, the end products of the cholesterol catabolic pathways, serve several important physiological functions, including solubilization of cholesterol, vitamins and other lipids in the intestine (, ; ). Because of their intrinsic toxicity, intracellular bile acid levels are tightly controlled by a complex regulatory cascade, which modulates their own synthesis. The molecular target of this feedback regulatory loop has been shown to be the CYP7A1 gene, encoding the rate-limiting enzyme of the ‘classical' cholesterol catabolic pathway (; ). Previous studies identified the nuclear receptor FXRα as the major hepatic bile acid sensor that governs bile acid synthesis and transport (; ; ). Bile acids are potent ligands of FXRα, which induces the expression of SHP (small heterodimer partner). Elevated levels of SHP in turn lead to transcriptional repression of the CYP7A1 gene, by inhibiting the activity of the nuclear receptor LRH-1 on the CYP7A1 promoter (; ). In line with this, mice deficient in SHP exhibit impaired feedback regulation of bile acid production, although compensatory, SHP-independent repression pathways can also operate (; ; ). SHP is an atypical orphan nuclear receptor, which lacks a DNA-binding domain (). It contains an N-terminal receptor dimerization domain, which mediates its recruitment to promoters via interaction with various nuclear receptors. Previous in vitro studies have identified a number of potential interaction partners for SHP, including LRH-1, HNF-4, ER, PPARs, PXR, CAR and NF-κB (, ; ; ; ; ; ). These observations indicate that SHP may regulate a broad array of genes in various biological pathways. SHP is expressed at low levels in the liver and is transiently induced by bile acid treatment (; ). Because bile acids can affect the expression of a variety of genes independently of SHP (; ; ), the identity of the bona fide targets of this nuclear receptor and its in vivo contribution to the feedback repression of genes involved in cholesterol catabolic cascade remained elusive.
Signal Transduction Processes - The Medical …
N2 - Aim: Bile acid synthesis is regulated by nuclear receptors including farnesoid X receptor (FXR) and small heterodimer partner (SHP), and by fibroblast growth factor 15/19 (FGF15/19). We hypothesized that hepatic cysteine sulfinic acid decarboxylase (CSAD) (a key enzyme in taurine synthesis) is regulated by bile acids (BA). The aim of this study was to investigate CSAD regulation by BA dependent regulatory mechanisms. Methods: Mice were fed a control diet or a diet supplemented with either 0.5% cholate or 2% cholestyramine. To study BA dependent pathways, we utilized GW4064 (FXR agonist), FGF19 or T-0901317 (liver X receptor [LXR] agonist) and Shp-/- mice. Tissue mRNA was determined by quantitative reverse transcription polymerase chain reaction. Amino acids were measured by high-performance liquid chromatography. Results: Mice supplemented with dietary cholate exhibited reduced hepatic CSAD mRNA while those receiving cholestyramine exhibited increased mRNA. Activation of FXR suppressed CSAD mRNA expression whereas CSAD expression was increased in Shp-/- mice. Hepatic hypotaurine concentration (the product of CSAD) was higher in Shp-/- mice with a corresponding increase in serum taurine conjugated BA. FGF19 administration suppressed hepatic cholesterol 7-α-hydroxylase (CYP7A1) mRNA but did not change CSAD mRNA expression. LXR activation induced CYP7A1 mRNA yet failed to induce CSAD mRNA expression. Conclusion: BA regulate CSAD mRNA expression in a feedback fashion via mechanisms involving SHP and FXR but not FGF15/19 or LXR. These findings implicate BA as regulators of CSAD mRNA via mechanisms shared with CYP7A1.