Bile Acid Synthesis and Utilization

A potential role of PXR in regulating bile acid synthesis was first implicated by the observation that treating rodents with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, repressed liver CYP7A1 activity (; ), which provides a molecular basis for cross-talk between bile acids and drug metabolism. A regulatory role of PXR in bile acid synthesis was subsequently confirmed by studies showing that PCN repressed CYP7A1 mRNA expression and biliary bile acid secretion, but failed to do so in PXR-deficient mice (). In human hepatocytes and liver cell line models, two groups showed that rifampicin-activated PXR repressed human CYP7A1 gene transcription by inhibiting the nuclear receptor, hepatocyte nuclear factor 4 alpha (HNF4α), and coactivator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) complex that is required for CYP7A1 gene transcription (; ). More recently, activation of PXR in the intestine was shown to induce FGF15 expression, and a PXR response element was identified in the promoter of the FGF15 gene (). These results suggest that drug or bile acid activation of intestinal PXR may mediate inhibition of CYP7A1 and bile acid synthesis. Whether PXR induces FGF19 in human hepatocytes remains to be determined. PXR induction of intestinal FGF19 was recently associated with promotion of colon tumor growth, implicating a link between PXR activation and anticancer drug resistance (). Interestingly, a recent study showed that mice lacking PXR fed a lithogenic diet had higher susceptibility to development of cholesterol gallstones, which is associated with decreased Cyp7a1 gene expression, reduced biliary bile acid secretion, and higher intestinal FGF15 expression ().

The end products of cholesterol utilization are the bile acids

Glossary | Linus Pauling Institute | Oregon State University

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.

Acetylation the addition of an acetyl group (-COCH 3) group to a molecule

Liver fibrosis in biliary atresia

Lipids (cholesterol and fatty acids) are essential nutriments and have a major impact on gene expression. Hence cholesterol intracellular concentration is precisely controlled by some complex mechanisms involving transcriptional regulations. The excess of cholesterol in cells is converted into oxysterols. These cholesterol metabolites are important signalisation molecules that modulate several transcription factors involved in cholesterol homeostasis. Schematically, regulation of cholesterol homeostasis is achieved by three different but complementary pathways: 1) endogeneous biosynthesis, which corresponds to the de novo synthesis of cholesterol and is controlled by sterol response element binding proteins (SREBPs); 2) the transport, intracellular absorption and esterification of the cholesterol; 3) the metabolic conversion into bile acids and steroid hormones. These three pathways are closely linked, however we will schematically detail the role of the orphan nuclear receptors on the modulation of these three levels of regulation. Phenotype analyses of knock-out or transgenic mice pointed out the respective role of the « enterohepatic » orphan nuclear receptors LXRα LXRβ, FXR, LRH-1, the nuclear receptor PPARα, and their heterodimeric partner RXR, as well as the peculiar receptor SHP. Complex feed-backs have thus been demonstrated. These transciptional regulations have several targets: the P450 cytochromes involved in the bile acid synthesis Cyp7a1 and Cyp8b1; the intestinal bile acid binding protein IBABP; the cholesteryl ester transfert protein CETP and phospholipid transfert protein PLTP, both involved in the HDL catabolism; the ABC cholesterol transporters ABCG1/ABC8 and ABCAI/ABCI. At last it seems that polyunsaturated fatty acids could activate LXRα transcription through its activation by PPARα. In the near future, the identification and study of new target genes by transcriptomic or proteomic analyses will allow a better understanding of lipid homeostasis in physiological as well as pathophysiological conditions.

Peripheral Mechanisms in Irritable Bowel Syndrome — …

N2 - Lipids (cholesterol and fatty acids) are essential nutriments and have a major impact on gene expression. Hence cholesterol intracellular concentration is precisely controlled by some complex mechanisms involving transcriptional regulations. The excess of cholesterol in cells is converted into oxysterols. These cholesterol metabolites are important signalisation molecules that modulate several transcription factors involved in cholesterol homeostasis. Schematically, regulation of cholesterol homeostasis is achieved by three different but complementary pathways: 1) endogeneous biosynthesis, which corresponds to the de novo synthesis of cholesterol and is controlled by sterol response element binding proteins (SREBPs); 2) the transport, intracellular absorption and esterification of the cholesterol; 3) the metabolic conversion into bile acids and steroid hormones. These three pathways are closely linked, however we will schematically detail the role of the orphan nuclear receptors on the modulation of these three levels of regulation. Phenotype analyses of knock-out or transgenic mice pointed out the respective role of the « enterohepatic » orphan nuclear receptors LXRα LXRβ, FXR, LRH-1, the nuclear receptor PPARα, and their heterodimeric partner RXR, as well as the peculiar receptor SHP. Complex feed-backs have thus been demonstrated. These transciptional regulations have several targets: the P450 cytochromes involved in the bile acid synthesis Cyp7a1 and Cyp8b1; the intestinal bile acid binding protein IBABP; the cholesteryl ester transfert protein CETP and phospholipid transfert protein PLTP, both involved in the HDL catabolism; the ABC cholesterol transporters ABCG1/ABC8 and ABCAI/ABCI. At last it seems that polyunsaturated fatty acids could activate LXRα transcription through its activation by PPARα. In the near future, the identification and study of new target genes by transcriptomic or proteomic analyses will allow a better understanding of lipid homeostasis in physiological as well as pathophysiological conditions.

BLACK SEED: Uses, Side Effects, Interactions and …

Bile acid synthesis regulates cholesterol homeostasis in hepatocytes. Cholesterol homeostasis is maintained by dietary uptake of cholesterol, cholesterol synthesis from acetyl‐CoA, and conversion of cholesterol to bile acids. Oxysterols are derived from cholesterol and bile acids. When intracellular cholesterol/oxysterol levels are high, steroid response element binding protein 2 (SREBP‐2) precursor (125 kDa) interacts with insulin induced gene 1/2 (Insig1/2) and is retained in endoplasmic reticulum (ER) membrane. When intracellular oxysterol levels are low, SREBP cleavage and activating protein (SCAP) escorts SREBP‐2 precursor to the Golgi apparatus, where sterol sensitive proteases S1P and S2P are activated to cleave a N‐terminal fragment (65 kDa), which is translocated to the nucleus to bind to the steroid response elements in the gene promoters of all cholesterogenic genes and stimulates cholesterol synthesis. Oxysterols activate LXRα, which induces gene transcription to stimulate bile acid synthesis in mice, but not humans. Bile acids (CDCA) activate farnesoid X receptor (FXR) to inhibit gene transcription and bile acid synthesis. This may lead to increased cholesterol levels and inhibited cholesterol synthesis and absorption of dietary cholesterol.