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(1988), Regulation of bile acid synthesis.

CA and are conjugated to glycine (G) and taurine (T). and are two key enzymes involved in amino conjugation of bile acids.

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Bile Acid Synthesis, Metabolism and Biological Functions

Bile acids homeostasis: activation of in the liver promotes several pathways (like the upregulation of the small heterodimer partner-1, ) that lead to the suppression of the Cyp7a1 and of the Cyp8b1, while the efflux from the hepatocyte is increased. signaling may also be involved.

T1 - Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

AB - 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.

Bile Acid Synthesis and Utilization

The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic acid (31%).

Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4α and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7α-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.

Since the last special review of cholesterol 7α-hydroxylase (CYP7A1) published in the Journal of Lipid Research in 1977 (), there has been remarkable progress on the molecular mechanisms of regulation of bile acid synthesis. The cloning of the key regulatory gene CYP7A1 about 20 years ago (–), followed by the identification of the bile acid-activated receptor farnesoid X receptor (FXR, NR1H4) 10 years later (–), has generated high interest in bile acid research. New functions of bile acids in metabolic regulation have been unraveled. It is now well recognized that bile acids are important signaling molecules that coordinately regulate a network of metabolic pathways, including lipid, glucose, drug, and energy metabolism (reviewed in Refs. –).

Regulation of bile acid synthesis

Furthermore, an important role for bile acids as signaling molecules hasemerged.

Two recent studies of liver conditional knockout of Lrh-1 in mice show that Cyp8b1 expression is abolished and CA is eliminated; however, basal Cyp7a1 expression is not affected and an FXR agonist GW4064 repressed Cyp7a1 expression (, ). These results suggest that LRH-1 may not be involved in FXR inhibition of CYP7A1 but is required for FXR inhibition of CYP8B1 gene transcription. This is consistent with the earlier finding that knockout of the Shp gene in mice did not prevent bile acid inhibition of CYP7A1 mRNA expression (, ). This raises the doubt that the FXR/SHP/LRH-1 pathway is involved in bile acid inhibition of CYP7A1 under normal physiological conditions. It should be noted that bile acid induction of SHP is very rapid and transient. It is likely that SHP is transiently induced by bile acids or inflammatory cytokines in acute phase response to liver injury and cholestasis and during liver regeneration () to protect liver against toxicity of bile acids and other metabolites (, ).

The molecular mechanisms of SHP inhibition of gene expression have been studied in transgenic mice overexpressing SHP in hepatocytes (). SHP transgenic mice have fat accumulation. Global gene expression profiling combined with chromatin immunoprecipitation assay reveals that SHP affects the genes involved in bile acid synthesis (CYP7A1, CYP8B1, and CYP7B1), conjugation (BAT), and transport (BSEP, NTCP, and MDR2) as expected. Interestingly SHP transgenic mice express lower levels of SR-B1 and CYP51b but higher levels of ABCA1, PPARγ, steroid response element binding protein-1c, CD36 (fatty acid transporter), fatty acid synthase, acyl-CoA carboxylase-1, and stearoyl-CoA desaturase-1 involved in fatty acid metabolism. These data suggest that SHP may play a role in downregulation of lipogenesis and protecting against steatosis. SHP alters chromatin configuration in SHP downregulated genes. Interestingly, SHP associates with unmodified and methylated-histone 3-Lys9 (H3K9) but not acetylated-H3K9. Furthermore, SHP interacts with histone deacetylase-1 (HDAC-1) and a histone methytransferase G9a (), suggesting that SHP repression of gene transcription by multiple steps involving histone deacetylation, followed by H3K9 methylation, and stable association of SHP to chromatin. Another study reports that SHP interacts with a repressor, mSin3A, and recruits chromatin remodeling complex Swi/Snf/Brm to CYP7A1 chromatin containing the bile acid response elements (). A follow-up study shows that SHP recruits HDACs and interacts with G9a to enhance SHP inhibition of CYP7A1 (). It has been shown that bile acids stimulate translocation of HDACs to the nucleus to assemble a repressor complex consisting of HDAC7, SHP, and a common nuclear receptor corepressor silencing mediator of retinoid and thyroid receptor to inhibit CYP7A1 (). Another nuclear receptor corepressor GPS2 interacts with SHP, LRH-1, HNF4α, and FXR and differentially regulates CYP7A1 and CYP8B1 (). It is not clear how bile acids induce or recruit these repressor complexes to inhibit CYP7A1 transcription.

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  • 15.08.1985 · Regulation of bile-acid synthesis

    Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat

  • Disorders of bile acid synthesis | SpringerLink

    Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat.

  • Bile Acid Synthesis | Annual Review of Physiology

    Bile Acid Synthesis

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The enzymes, regulation, and genetics of bile acid synthesis

Bile acid synthesis is feedback inhibited by bile acids returning to the liver via enterohepatic circulation to inhibit CYP7A1 (). Currently, there are two FXR-dependent mechanisms for bile acid inhibition of CYP7A1 gene transcription (). In the liver, FXR induces SHP to inhibit CYP7A1. In the intestine, FXR induces FGF19 to activate liver FGF receptor 4 (FGFR4) signaling to inhibit CYP7A1.

Bile acid synthesis is thought to be ..

In humans, about 0.2–0.6 g of bile acids are synthesized daily in human liver. The enterohepatic circulation of bile acids is illustrated in . Conjugated bile acids are secreted into bile by canalicular bile salt export pump (BSEP; ABCB11) and stored in the gallbladder. Bile acids are spilled over into sinusoid blood when concentrations increase in the hepatocytes. Bile acids in blood circulation are reabsorbed when passing through the renal tubules in the kidney and are circulated back to the liver through systemic circulation. Some bile acids secreted in the bile duct are reabsorbed in the cholangiocytes and recycled back to hepatoytes (the cholangiohepatic shunt). After each meal, gallbladder contraction empties bile acids into the intestinal tract. When passing through the intestinal tract, some bile acids are reabsorbed in the upper intestine by passive diffusion, but most bile acids (95%) are reabsorbed in the ileum by apical sodium-dependent bile acid transporter (ASBT) located in the brush border membrane. Bile acids are transdiffused across the enterocyte to the basolateral membrane where the organic solute transporter α and β heterdimer (OSTα/OSTβ) effluxes bile acids into portal blood circulation, transported to the sinusoid, and taken up by Na+-dependent taurocholate cotransport peptide (NTCP) into hepatocytes. In the colon, DCA is reabsorbed and recycled with CA and CDCA to the liver. A bile acid pool of about 3 g is recycled 4–12 times a day. Bile acids lost in the feces (0.2–0.6 g/day) are replenished by de novo synthesis in the liver to main a constant bile acid pool.

Bile Acids and Metabolic Regulation | Diabetes Care

Regulation of the rate-limiting enzyme in bile acid biosynthetic pathway CYP7A1 has been studied extensively. The CYP7A1 mRNA transcripts in the 3′-untranslated region are unusually long () and have a very short half-life of about 30 min (, ). It has been reported that bile acids reduce CYP7A1 mRNA stability via the bile acid response elements located in the 3′-untranslated region (, ). Numerous studies have demonstrated that bile acids, steroid hormones, inflammatory cytokines, insulin, and growth factors inhibit CYP7A1 transcription through the 5′-upstream region of the promoter (–).

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