Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher, P; Kitto, Jennifer L.; Petrowski, Mary; Tangirala, Rajendra K.; Bischoff, Eric D.; Schulman, Ira G.; Westin, Stefan

doi:10.1074/jbc.m302128200

Cited by 169 publications

(107 citation statements)

References 30 publications

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“…Because this phenomenon was not observed in mouse, regulation of both genes by FXR exhibits a species difference between rat and mouse (26). Actually, neither VLACSR nor BAT gene was induced in wild-type mice treated with cholic acid, a ligand for FXR (data not shown).…”

Section: Expression Of Genes Involved In Ba Conjugationmentioning

confidence: 91%

“…It was reported that the expression of BAL and BAT is induced by treatment with ligands for the farnesoid X receptor (FXR) in rat, and this induction was due to the binding of FXR to FXR-binding sites in their promoter regions (26). Because this phenomenon was not observed in mouse, regulation of both genes by FXR exhibits a species difference between rat and mouse (26).…”

Section: Expression Of Genes Involved In Ba Conjugationmentioning

confidence: 91%

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Hepatocyte Nuclear Factor 4α Is a Central Regulator of Bile Acid Conjugation

Inoue

et al. 2004

Journal of Biological Chemistry

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Hepatocyte nuclear factor 4␣ (HNF4␣) has an important role in regulating the expression of liver-specific genes. Because bile acids are produced from cholesterol in liver and many enzymes involved in their biosynthesis are preferentially expressed in liver, the role of HNF4␣ in the regulation of bile acid production was examined. In mice, unconjugated bile acids are conjugated with taurine by the liver-specific enzymes, bile acid-CoA ligase and bile acid-CoA:amino acid N-acyltransferase (BAT). Mice lacking hepatic HNF4␣ expression exhibited markedly decreased expression of the very long chain acyl-CoA synthase-related gene (VLACSR), a mouse candidate for bile acid-CoA ligase, and BAT. This was associated with markedly elevated levels of unconjugated and glycine-conjugated bile acids in gallbladder. HNF4␣ was found to bind directly to the mouse VLACSR and BAT gene promoters, and the promoter activities were dependent on HNF4␣-binding sites and HNF4␣ expression. In conclusion, HNF4␣ plays a central role in bile acid conjugation by direct regulation of VLACSR and BAT in vivo.

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Section: Expression Of Genes Involved In Ba Conjugationmentioning

confidence: 91%

Section: Expression Of Genes Involved In Ba Conjugationmentioning

confidence: 91%

Hepatocyte Nuclear Factor 4α Is a Central Regulator of Bile Acid Conjugation

Inoue

et al. 2004

Journal of Biological Chemistry

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“…Bile acids are natural ligands for the nuclear receptor, farnesoid X receptor (FXR), and the plasma membranebound bile acid receptor TGR5 [also known as G protein-coupled bile acid receptor 1 (Gpbar1); membrane-type receptor for bile acids (M-BAR)]. Through activation of these receptors bile acids regulate lipid (9-11), glucose (12-16), and energy homeostasis (17) in addition to regulating their own synthesis (18), conjugation (19), transport (20)(21)(22), and detoxification (19,23,24). The global signaling capacity of bile acids is currently unclear; however, the expression of bile acid receptors FXR and TGR5 in tissues outside of the enterohepatic circulation, including the kidney (25) and heart (26, 27), suggests a greater role throughout the body.…”

mentioning

confidence: 99%

Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Swann

Want

Geier

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

651

476

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We elucidate the detailed effects of gut microbial depletion on the bile acid sub-metabolome of multiple body compartments (liver, kidney, heart, and blood plasma) in rats. We use a targeted ultraperformance liquid chromatography with time of flight mass-spectrometry assay to characterize the differential primary and secondary bile acid profiles in each tissue and show a major increase in the proportion of taurine-conjugated bile acids in germ-free (GF) and antibiotic (streptomycin/penicillin)-treated rats. Although conjugated bile acids dominate the hepatic profile (97.0 ± 1.5%) of conventional animals, unconjugated bile acids comprise the largest proportion of the total measured bile acid profile in kidney (60.0 ± 10.4%) and heart (53.0 ± 18.5%) tissues. In contrast, in the GF animal, taurine-conjugated bile acids (especially taurocholic acid and tauro-β-muricholic acid) dominated the bile acid profiles (liver: 96.0 ± 14.5%; kidney: 96 ± 1%; heart: 93 ± 1%; plasma: 93.0 ± 2.3%), with unconjugated and glycine-conjugated species representing a small proportion of the profile. Higher free taurine levels were found in GF livers compared with the conventional liver (5.1-fold; P < 0.001). Bile acid diversity was also lower in GF and antibiotic-treated tissues compared with conventional animals. Because bile acids perform important signaling functions, it is clear that these chemical communication networks are strongly influenced by microbial activities or modulation, as evidenced by farnesoid X receptor-regulated pathway transcripts. The presence of specific microbial bile acid co-metabolite patterns in peripheral tissues (including heart and kidney) implies a broader signaling role for these compounds and emphasizes the extent of symbiotic microbial influences in mammalian homeostasis.farnesoid X receptor | gut microbiota | TGR5 | ultra-performance liquid chromatography mass spectrometry | G protein-coupled bile acid receptor 1 T he importance of gut microbiome variation in relation to human health and diverse diseases is now well-recognized (1-4). The microbiome is a virtual organ that performs many digestive and metabolic functions for the host, including enhanced calorific recovery from ingested foods and degradation of complex plant polysaccharides. Microbial communities have coevolved with man and show remarkable diversity dependent on topographical location and interperson variability (5). Co-evolution has refined the microbiome of organisms to a state where metabolic complementarity exists within the microbiota (6), and important biosynthetic/ metabolic pathways are provided for the host that significantly extend host metabolic capacity (3). As such, the mammalian host can be considered a superorganism (7), whose metabolism is the sum of that of both the host and the collective microbial community. The enterohepatic circulation provides a vehicle for this transgenomic metabolism, and bile acids, whose functional role in the global mammalian system is multifaceted, are an important class of metabolites that u...

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“…Baat mRNA is upregulated by cholestyramine (a bile acid binding resin) treatment in mouse liver [139], whereas in rat, BAAT activity is unchanged by cholestyramine treatment [135], showing a distinct species difference. Baat is regulated by the farnesoid X receptor (FXR) in the rat via an inverted repeat 1 (IR-1) element located in the first intron of the gene and Baat mRNA levels were increased in rats following treatment with a synthetic FXR ligand [161]. Baat expression is also regulated by the hepatocyte nuclear factor 4 alpha (HNF-4α) via a response element in the promoter and expression of the Baat mRNA is not detectable in the HNF-4α knockout mouse, resulting in markedly elevated levels of unconjugated bile acids in gallbladder in this knockout model [162].…”

Section: Regulation Of Acots and Acyltransferases In Peroxisomesmentioning

confidence: 99%