Changes in the pattern of bile acids in the nuclei of rat liver cells during hepatocarcinogenesis

2002 ◽  
Vol 102 (2) ◽  
pp. 143-150 ◽  
Author(s):  
M.E. MENDOZA ◽  
M.J. MONTE ◽  
M.Y. EL-MIR ◽  
M.D. BADIA ◽  
J.J.G. MARIN
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Rat Liver ◽  
Bile Acid Pool ◽  
Adult Rats ◽  
Isolated Nuclei ◽  
Acid Pool ◽  
Liver Homogenates

Bile acids reach the nuclei of hepatocytes, where they may play an important role in controlling gene expression by binding to nuclear receptors. In previous studies, changes in the amounts of the different molecular species of bile acids in the hepatocyte nucleus during rat liver regeneration have been reported. The aim of the present work was to investigate whether this also occurs during rat hepatocarcinogenesis. Liver cell nuclei were isolated after homogenization of livers from healthy adult rats (controls) and from rats at different time points during chemically induced hepatocarcinogenesis, corresponding to the stages of foci (12 weeks), hepatoma (20 weeks) and carcinoma (32 weeks). Bile samples from the cannulated common bile duct were collected for 1h from different sets of animals undergoing hepatocarcinogenesis. Bile acids in bile, liver homogenates and isolated nuclei were measured by GC-MS. Because the yield of nuclei isolated changed during the course of hepatocarcinogenesis (control, 20.1%; 12 weeks, 23.6%; 20 weeks, 7.8%; 32 weeks, 5.1%), amounts of bile acids in nuclei were corrected for the amount of DNA in each preparation. During hepatocarcinogenesis, bile acid concentrations in liver homogenates were reduced to approximately half the values obtained in control livers, while the levels of bile acids in both isolated nuclei and bile were not decreased. Hepatocarcinogenesis induced changes in the composition of bile acid pools. These were manifest as an increase in the proportion of cholic acid and a decrease in that of ursodeoxycholic acid in both bile and liver. These modifications differed from the changes seen in the nuclear bile acid pool, where a decrease in the proportion of cholic acid together with an increase in that of ursodeoxycholic acid were the major changes observed during hepatocarcinogenesis. With regard to the ‘flat’ bile acids (allo-cholic acid plus Δ5- or Δ4-unsaturated bile acids), a marked hepatocarcinogenesis-induced increase in the output of these species in bile was found. However, these bile acids were only found in liver homogenates at the hepatoma stage, whereas they were not detected in isolated nuclei at any stage of hepatocarcinogenesis. In summary, these results support the existence of a bile acid pool in hepatocyte nuclei whose composition differs from that of the extranuclear bile acid pool. Moreover, they indicate that, during hepatocarcinogenesis, the composition of the nuclear pool undergoes important alterations.

Overexpression of sterol 12α-hydroxylase (CYP8b1): Effect on rates of cholic acid (CA) synthesis and alteration in bile acid pool composition

2001 ◽  
Vol 120 (5) ◽  
pp. A1
Author(s):  
William M. Pandak ◽  
Phillip B. Hylemon ◽  
Patricia Bohdan ◽  
Ingemar Bjorkhem ◽  
Gosta Eggertsen ◽  
...  
Keyword(s):  
Bile Acid ◽  
Cholic Acid ◽  
Bile Acid Pool ◽  
Acid Pool

scholarly journals Antibiotic-Induced Changes in Microbiome-Related Metabolites and Bile Acids in Rat Plasma

Metabolites ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 242
Author(s):  
Véronique de Bruijn ◽  
Christina Behr ◽  
Saskia Sperber ◽  
Tilmann Walk ◽  
Philipp Ternes ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Community Analysis ◽  
Rat Plasma ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Administration Routes ◽  
Plasma Metabolome ◽  
Induced Changes ◽  
Plasma Metabolite

Various environmental factors can alter the gut microbiome’s composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were compared to distinguish between microbiome-derived or -associated and systemic changes in the plasma metabolome. The resulting changes in the plasma metabolome were compared to the effects of a third reference compound, roxithromycin, which is readily bioavailable. A community analysis revealed that the oral administration of vancomycin and roxithromycin in particular leads to an altered microbial population. Antibiotic-induced changes depending on the administration routes were observed in plasma metabolite levels. Indole-3-acetic acid (IAA) and hippuric acid (HA) were identified as key metabolites of microbiome modulation, with HA being the most sensitive. Even though large variations in the plasma bile acid pool between and within rats were observed, the change in microbiome community was observed to alter the composition of the bile acid pool, especially by an accumulation of taurine-conjugated primary bile acids. In-depth investigation of the relationship between microbiome variability and their functionality, with emphasis on the bile acid pool, will be necessary to better assess the potential adverseness of environmentally induced microbiome changes.

scholarly journals Increased cholesterol 7α-hydroxylase expression and size of the bile acid pool in the lactating rat

2008 ◽  
Vol 294 (4) ◽  
pp. G1009-G1016 ◽  
Author(s):  
Clavia Ruth Wooton-Kee ◽  
David E. Cohen ◽  
Mary Vore
Keyword(s):  
Bile Acid ◽  
Protein Expression ◽  
Mrna Expression ◽  
Bile Acids ◽  
Fold Increase ◽  
Bile Acid Pool ◽  
Hydrophobicity Index ◽  
Acid Pool ◽  
Bile Acid Transporters ◽  
Cholic Acids

Maximal bile acid secretory rates and expression of bile acid transporters in liver and ileum are increased in lactation, possibly to facilitate increased enterohepatic recirculation of bile acids. We determined changes in the size and composition of the bile acid pool and key enzymes of the bile acid synthetic pathway [cholesterol 7α-hydroxylase (Cyp7a1), sterol 27-hydroxylase (Cyp27a1), and sterol 12α-hydroxylase (Cyp8b1)] in lactating rats relative to female virgin controls. The bile acid pool increased 1.9 to 2.5-fold [postpartum (PP) days 10, 14, and 19–23], compared with controls. A 1.5-fold increase in cholic acids and a 14 to 20% decrease in muricholic acids in lactation significantly increased the hydrophobicity index. In contrast, the hepatic concentration of bile acids and small heterodimer partner mRNA were unchanged in lactation. A 2.8-fold increase in Cyp7a1 mRNA expression at 16 h (10 h of light) demonstrated a shift in the diurnal rhythm at day 10 PP; Cyp7a1 protein expression and cholesterol 7α-hydroxylase activity were significantly increased at this time and remained elevated at day 14 PP but decreased to control levels by day 21 PP. There was an overall decrease in Cyp27a1 mRNA expression and a 20% decrease in Cyp27a1 protein expression, but there was no change in Cyp8b1 mRNA or protein expression at day 10 PP. The increase in Cyp7a1 expression PP provides a mechanism for the increase in the bile acid pool.

Cholestasis induced by Sulphated Glycolithocholic Acid in the Rat: Protection by Endogenous Bile Acids

1985 ◽  
Vol 68 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Folkert Kuipers ◽  
Rick Havinga ◽  
Roel J. Vonk
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Biliary Excretion ◽  
Hepatic Clearance ◽  
Recovery Phase ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Hepatotoxic Effect ◽  
Biliary Excretion Rate ◽  
Bile Production

1. Sulphated glycolithocholic acid (SGLC) causes cholestasis in experimental animals, despite its sulphated form. In the present study, the cholestatic potency and the pharmacokinetics of SGLC were investigated in rats under two conditions: (a) in the presence of an intact circulating bile acid pool and (b) after exhaustion of the bile acid pool by 24 h of bile diversion. 2. Intravenous administration of SGLC (8 μmol/ 100 g body weight) to rats with an intact bile acid pool did not cause cholestasis. However, biliary phospholipid and cholesterol concentrations were reduced by 40% and 29% respectively during the first hour after administration. When the same dose of the bile acid was injected in rats with a 24 h biliary drainage, a complete cessation of bile production was observed within 1 h. Twelve hours after the onset of cholestasis, bile production gradually increased again, showed a marked overshoot, and reached control levels after 3 days. In the recovery phase, biliary phospholipid and cholesterol concentrations were greatly reduced. 3. The absence of endogenous bile acids did not change the hepatic clearance rate of a tracer dose of radiolabelled SGLC, but markedly decreased its biliary excretion rate. 4. It was concluded that the hepatotoxic effect of SGLC is much more pronounced in rats with an exhausted bile acid pool, possibly due to a slower biliary excretion of the toxic compound. This phenomenon may have clinical implications for patients with a contracted bile acid pool.

Pre-replicative phase-related changes in bile acid-induced choleresis in the regenerating rat liver

1990 ◽  
Vol 78 (1) ◽  
pp. 55-62 ◽  
Author(s):  
J. J. Garcia-Marin ◽  
P. Regueiro ◽  
J. C. Perez-Antona ◽  
G. R. Villanueva ◽  
F. Perez-Barriocanal
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Cholic Acid ◽  
Rat Liver ◽  
Bile Flow ◽  
Acid Output ◽  
Liver Weight ◽  
Bicarbonate Secretion ◽  
Regenerating Rat Liver ◽  
Bicarbonate Output

1. During the pre-replicative phase of the regenerating rat liver some interesting changes occur, which might selectively modify some mechanisms involved in bile formation, such as those responsible for the hypercholeretic effect of ursodeoxycholic acid. The aim of the present work was to gain information on this point. 2. Anaesthetized male Wistar rats (∼ 250 g) were used. The animals underwent two-thirds hepatectomy 1, 6 or 12 h before collection of bile samples was begun. Very early after hepatectomy (1 h) spontaneous bile flow and bile acid output were increased. Both returned to values not significantly different from those of the controls at 6 h. Bile flow increased again at the end of the pre-replicative phase. Taurocholate infusion (200 nmol min−1 g−1 calculated liver weight) induced increases in bile flow and bile acid output that were similar in both the control and hepatectomized rats, regardless of the time of the pre-replicative phase considered. 3. Cholic acid and ursodeoxycholic acid were infused (300 nmol min−1 g−1 calculated liver weight) into control and partially hepatectomized rats (at the mid-point of the pre-replicative phase, i.e. 6 h after surgical liver resection). Cholic acid-induced bile flow, bile acid and bicarbonate output expressed per g of remaining liver were similar in control and in hepatectomized rats. By contrast, ursodeoxycholic acid-induced choleresis was profoundly altered during the pre-replicative phase. As expressed per g of remaining liver, bile flow was markedly reduced (− 17%, P < 0.05), in spite of total bile acid output being greatly increased (+ 148%, P < 0.001). The reduced choleretic effect of ursodeoxycholic acid may be due to a lowered stimulation of bicarbonate secretion (− 41%, P < 0.01). 4. Factors known to reduce ursodeoxycholic acid-induced bicarbonate secretion into bile, such as decreased plasma bicarbonate concentrations and lowered total hepatic carbonic anhydrase activity, cannot account for the loss of the ability of ursodeoxycholic acid to stimulate bicarbonate secretion during the pre-replicative phase. However, the bile acid conjugation patterns were dramatically altered early after hepatectomy (6 h). In bile from the control animals the major ursodeoxycholic acid conjugation was with glycine, whereas in hepatectomized rats it was with taurine. 5. In summary, our results indicate that during the prereplicative phase of the regenerating rat liver, a loss occurs in the hypercholeretic effect of bile acids such as ursodeoxycholic acid. However, the choleretic effect of non-hypercholeretic bile acids such as cholic acid and taurocholic acid was not altered. Moreover, the existence of a relationship between the decrease in bile flow and bicarbonate output and the marked increase in the secretion of low-pKa conjugated bile acid derivatives is suggested.

scholarly journals Nuclear and cytosolic distribution of conjugated cholic acid and radiolabelled glycocholic acid in rat liver

1979 ◽  
Vol 178 (1) ◽  
pp. 71-78 ◽  
Author(s):  
R C Strange ◽  
G J Beckett ◽  
I W Percy-Robb
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholic Acid ◽  
Rat Liver ◽  
Superior Mesenteric Vein ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Acid Receptor ◽  
Glycocholic Acid ◽  
Bile Acid Receptor

1. Normally fed and cholestyramine-treated rats were injected through the superior mesenteric vein with different amounts of radiolabelled glycoholic acid and the appearance of radioactivity in bile was measured. 2. In normally fed rats radioactivity appeared in bile within 30 s of injection and reached a maximum after 2 1/2 min; in the cholestyramine-treated animals the appearance of radioactivity was slower and less of the injected material was excreted into bile. 3. At 10 min after injection, livers were removed and the amounts of radioactive glycoholic acid and endogenous cholic acid conjugates in nuclei and cytosol were determined; most of the bile acid was found in the cytosol, only small amounts being found in nuclei. 4. Nuclear preparations from both normally fed and cholestyramine-fed rats were extracted with KCl (0.4 M) in an attempt to identify a putative bile acid receptor, but no such receptor was found. 5. Regulation of bile acid synthesis does not involve nuclear binding of bile acids.

scholarly journals On the Conversion of 3alpha,7alpha,12alpha-Trihydroxycoprostanic Acid to Cholic Acid in Rat Liver Homogenates. Bile Acids and Steroids. 46.

1957 ◽  
Vol 11 ◽  
pp. 836-838 ◽  
Author(s):  
S. Bergström ◽  
R. J. Bridgwater ◽  
U. Gloor ◽  
Arne Magnéli ◽  
Arne Magnéli ◽  
...  
Keyword(s):  
Bile Acids ◽  
Cholic Acid ◽  
Rat Liver ◽  
Liver Homogenates

scholarly journals Metagenomic analysis of bile salt biotransformation in the human gut microbiome

2019 ◽  
Author(s):  
Promi Das ◽  
Simonas Marcišauskas ◽  
Boyang Ji ◽  
Jens Nielsen
Keyword(s):  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Salt ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Healthy Controls ◽  
Bile Acid Pool ◽  
Metabolomics Data ◽  
Acid Pool ◽  
Secondary Bile Acids

Abstract Background: In the biochemical milieu of human colon, bile acids act as signaling mediators between the host and its gut microbiota. Biotransformation of primary to secondary bile acids have been known to be involved in the immune regulation of human physiology. Several 16S amplicon-based studies with inflammatory bowel disease (IBD) subjects were found to have an association with the level of fecal bile acids. However, a detailed investigation of all the bile salt biotransformation genes in the gut microbiome of healthy and IBD subjects has not been performed. Results: Here, we report a comprehensive analysis of the bile salt biotransformation genes and their distribution at the phyla level. Based on the analysis of shotgun metagenomes, we found that the IBD subjects harbored a significantly lower abundance of these genes compared to the healthy controls. Majority of these genes originated from Firmicutes in comparison to other phyla. From metabolomics data, we found that the IBD subjects were measured with a significantly low level of secondary bile acids and high levels of primary bile acids compared to that of the healthy controls. Conclusions: Our bioinformatics-driven approach of identifying bile salt biotransformation genes predicts the bile salt biotransformation potential in the gut microbiota of IBD subjects. The functional level of dysbiosis likely contributes to the variation in the bile acid pool. This study sets the stage to envisage potential solutions to modulate the gut microbiome with the objective to restore the bile acid pool in the gut.

scholarly journals Secondary bile acid ursodeoxycholic acid (UDCA) alters weight, the gut microbiota, and the bile acid pool in conventional mice

2019 ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa Rivera ◽  
Jingwei Cai ◽  
Andrew D. Patterson ◽  
Casey M. Theriot
Keyword(s):  
Community Structure ◽  
Bile Acid ◽  
Microbial Community ◽  
Gut Microbiota ◽  
Ursodeoxycholic Acid ◽  
Microbial Community Structure ◽  
Cecal Content ◽  
Bile Acid Pool ◽  
Acid Pool ◽  
Gut Microbial Community

AbstractUrsodeoxycholic acid (commercially available as Ursodiol) is a naturally occurring bile acid that is used to treat a variety of hepatic and gastrointestinal diseases. Ursodiol can modulate bile acid pools, which have the potential to alter the gut microbiota community structure. In turn, the gut microbial community can modulate bile acid pools, thus highlighting the interconnectedness of the gut microbiota-bile acid-host axis. Despite these interactions, it remains unclear if and how exogenously administered ursodiol shapes the gut microbial community structure and bile acid pool. This study aims to characterize how ursodiol alters the gastrointestinal ecosystem in conventional mice. C57BL/6J wildtype mice were given one of three doses of ursodiol (50, 150, or 450 mg/kg/day) by oral gavage for 21 days. Alterations in the gut microbiota and bile acids were examined including stool, ileal, and cecal content. Bile acids were also measured in serum. Significant weight loss was seen in mice treated with the low and high dose of ursodiol. Alterations in the microbial community structure and bile acid pool were seen in ileal and cecal content compared to pretreatment, and longitudinally in feces following the 21-day ursodiol treatment. In both ileal and cecal content, members of the Lachnospiraceae family significantly contributed to the changes observed. This study is the first to provide a comprehensive view of how exogenously administered ursodiol shapes the gastrointestinal ecosystem. Further studies to investigate how these changes in turn modify the host physiologic response are important.ImportanceUrsodeoxycholic acid (commercially available as ursodiol) is used to treat a variety of hepatic and gastrointestinal diseases. Despite its widespread use, how ursodiol impacts the gut microbial community structure and bile acid pool remains unknown. This study is the first to provide a comprehensive view of how exogenously administered ursodiol shapes the gastrointestinal ecosystem. Ursodiol administration in conventional mice resulted in significant alterations in the gut microbial community structure and bile acid pool, indicating that ursodiol has direct impacts on the gut microbiota-bile acid-host axis which should be considered when this medication is administered.Bile Acid AbbreviationsαMCA – α–Muricholic acid; βMCA –β–Muricholic acid; ωMCA –ω–Muricholic acid; CA – Cholic acid; CDCA – Chenodeoxycholic acid; DCA – Deoxycholic acid; GCDCA – Glycochenodeoxycholic acid; GDCA – Glycodeoxycholic acid; GLCA – Glycolithocholic acid; GUDCA – Glycoursodeoxycholic acid; HCA – Hyodeoxycholic acid; iDCA – Isodeoxycholic acid; iLCA – Isolithocholic acid; LCA – Lithocholic acid; TCA – Taurocholic acid; TCDCA – Taurochenodeoxycholic acid; TDCA – Taurodeoxycholic acid; THCA – Taurohyodeoxycholic acid; TUDCA – Tauroursodeoxycholic acid; TβMCA – Tauro-β-muricholic acid; TωMCA –Tauro ω-muricholic acid; UDCA – Ursodeoxycholic acid.

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