The effect of cholesterol feeding on gallbladder bile acids of the rabbit. Evidence that lithocholic acid is a primary bile acid in the rabbit.
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ABSTRACT:
SUBMITTER: Taylor W
PROVIDER: S-EPMC1163312 | biostudies-other | 1981 Sep
REPOSITORIES: biostudies-other
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Project description:Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non-metabolizable analog of UDCA, 6-methyl-UDCA (6-MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC-dextran uptake and caspase-3 cleavage, respectively. Cecal bile acids were measured by HPLC-MS/MS. UDCA and LCA, but not 6-MUDCA, were protective against DSS-induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase-3 cleavage both in DSS-treated mice and in an in vitro model of cytokine-induced epithelial injury. HPLC-MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted.
| S-EPMC7305237 | biostudies-literature
Project description:An improved ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method was established for the simultaneous analysis of various bile acids (BA) and applied to investigate liver BA content in C57BL/6 mice fed 1% cholic acid (CA), 0.3% deoxycholic acid (DCA), 0.3% chenodeoxycholic acid (CDCA), 0.3% lithocholic acid (LCA), 3% ursodeoxycholic acid (UDCA), or 2% cholestyramine (resin). Results indicate that mice have a remarkable ability to maintain liver BA concentrations. The BA profiles in mouse livers were similar between CA and DCA feedings, as well as between CDCA and LCA feedings. The mRNA expression of Cytochrome P450 7a1 (Cyp7a1) was suppressed by all BA feedings, whereas Cyp7b1 was suppressed only by CA and UDCA feedings. Gender differences in liver BA composition were observed after feeding CA, DCA, CDCA, and LCA, but they were not prominent after feeding UDCA. Sulfation of CA and CDCA was found at the 7-OH position, and it was increased by feeding CA or CDCA more in male than female mice. In contrast, sulfation of LCA and taurolithocholic acid (TLCA) was female-predominant, and it was increased by feeding UDCA and LCA. In summary, the present systematic study on BA metabolism in mice will aid in interpreting BA-mediated gene regulation and hepatotoxicity.
| S-EPMC2952563 | biostudies-other
Project description:Purpose:To further explore the molecular mechanisms of LCA treatment underlying its tumor suppressive functions. Methods:For the NOZ cells cultures, there were two different conditions performed in biological triplicates: (I) mock (DMSO), (II) 150 μM LCA for 24 h. A total amount of 1 µg RNA per sample was used as input material for the RNA sample preparations. Sequencing libraries were generated using NEBNext® UltraTM RNA Library Prep Kit for Illumina® (NEB, USA) following manufacturer’s recommendations and index codes were added to attribute sequences to each sample. The clustering of the index-coded samples was performed on a cBot Cluster Generation System using TruSeq PE Cluster Kit v3-cBot-HS (Illumina) according to the manufacturer’s instructions. After cluster generation, the library preparations were sequenced on an Illumina Novaseq platform and 150 bp paired-end reads were generated. Paired t-test was used to normalize and statistically analyze the data. The threshold we set to screen for upregulated and downregulated genes with a fold change >0 and a padj-value < 0.05. Hierarchical clustering was performed and a heat map was constructed with edgeR R package (3.18.1) to visualize differential mRNA expression. Gene set enrichment analysis was conducted with the local version of the GSEA analysis tool http://www.broadinstitute.org/gsea/index.jsp. Results: By means of RNA-seq and subsequent data analysis with volcano plot and hierarchical clustering, we found that LCA treatment led to a different gene expression profile with the upregulation of 3607 genes and the downregulation of 3501genes compared with those in cells treated with mock. Gene Set Enrichment Analysis (GSEA) suggested that alanine, aspartate, and glutamate metabolism pathways were top-listed in the inhibitory regulation of LCA, and the heatmap plots showed that the pathways involved a set of 35genes. In addition, qRT-PCR was used to confirm the expression of several metabolism genes including GLS, ASS1, CPS1, ASNS, ABAT, and ADSSL. We were particularly interested in the commonly downregulated GLS in both NOZ and EH-GB1 cells, which mediates glutamate and glutamine metabolism. As the result, protein levels of GLS were dramatically inhibited by LCA in NOZ and EH-GB1 cells in a time-dependent manner as compared with the untreated cancer cells, Conclusion: GLS was a downstream effector of LCA treatment in gallbladder cancer.
2023-12-31 | GSE192577 | GEO
Project description:Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles ("Lp-X") in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease.
| S-EPMC7112145 | biostudies-literature
Project description:Background & aimsAs the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload.MethodsWild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy.ConclusionsBA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.
| S-EPMC7872982 | biostudies-literature
Project description:BackgroundThe development of gallbladder disease (GBD) is related to bile acid (BA) metabolism, and the rate of BA circulation increases the risk of biliary cancer. However, it is unclear whether patterns of circulating bile acids (BAs) change in patients with benign GBDs such as gallbladder stones and polyps. Herein, we compared and characterised plasma BA profiles in patients with cholecystolithiasis and non-neoplastic polyps with healthy controls, and explored relationships between plasma BA profiles, demographics, and laboratory test indices.MethodsA total of 330 subjects (13 healthy controls, 292 cholecystolithiasis and 25 non-neoplastic polyps) were recruited and plasma BA profiles including 14 metabolites from patients with pathologically confirmed cholecystolithiasis and non-neoplastic polyps were compared with controls. BAs were quantitated by liquid chromatography and mass spectrometry, and statistical and regression analyses of demographics and laboratory test indices were performed.ResultsFemales displayed a higher burden of GBD than males (63.36% cholecystolithiasis, 60% non-neoplastic polyps). Cholecystolithiasis and non-neoplastic polyps were associated with increased plasma total secondary BAs, while levels of primary BAs were lower than in healthy controls. Plasma ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycyurdeoxycholic acid (GUDCA), taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) were decreased significantly in GBDs, and ursodeoxycholic acid (UDCA) was negatively correlated with white blood cell count and neutrophil percentage.ConclusionsSecondary BA levels were higher in patients with cholecystolithiasis and non-neoplastic polyps. White blood cell count and percentage of neutrophil in peripheral blood were negatively correlated with UDCA, indicating an anti-inflammation effect of UDCA.
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Project description:Transforming growth factor-? (TGF?) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGF? regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGF? expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter ? (OST?) expression were markedly decreased in Smad3-null mice, whereas TGF? induced LPCAT4 and OST? expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGF?-induced LPCAT4 and OST? expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGF?-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury.
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Project description:1. When rat-liver mitochondria were incubated with [4-(14)C]cholesterol in the presence of a soluble supernatant fraction, various steroids more polar than cholesterol were formed. These included 3beta-hydroxycholest-5-en-26-oic acid, 3beta-hydroxychol-5-enoic acid, lithocholic acid, chenodeoxycholic acid and alpha- and beta-muricholic acids. 2. All the radioactive C(24) bile acids recovered were in conjugated form, probably as taurine conjugates. 3. The formation of 3beta-hydroxychol-5-enoic acid from cholesterol shows that liver mitochondria are capable of carrying out the oxidative removal of the isopropyl unit of the side chain before any modification has occurred in the ring system.
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Project description:Bile acids (BAs) are known to regulate their own homeostasis, but the potency of individual bile acids is not known. This study examined the effects of cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) on expression of BA synthesis and transport genes in human primary hepatocyte cultures. Hepatocytes were treated with the individual BAs at 10, 30, and 100?M for 48 h, and RNA was extracted for real-time PCR analysis. For the classic pathway of BA synthesis, BAs except for UDCA markedly suppressed CYP7A1 (70-95%), the rate-limiting enzyme of bile acid synthesis, but only moderately (35%) down-regulated CYP8B1 at a high concentration of 100?M. BAs had minimal effects on mRNA of two enzymes of the alternative pathway of BA synthesis, namely CYP27A1 and CYP7B1. BAs increased the two major target genes of the farnesoid X receptor (FXR), namely the small heterodimer partner (SHP) by fourfold, and markedly induced fibroblast growth factor 19 (FGF19) over 100-fold. The BA uptake transporter Na(+)-taurocholate co-transporting polypeptide was unaffected, whereas the efflux transporter bile salt export pump was increased 15-fold and OST?/? were increased 10-100-fold by BAs. The expression of the organic anion transporting polypeptide 1B3 (OATP1B3; sixfold), ATP-binding cassette (ABC) transporter G5 (ABCG5; sixfold), multidrug associated protein-2 (MRP2; twofold), and MRP3 (threefold) were also increased, albeit to lesser degrees. In general, CDCA was the most potent and effective BA in regulating these genes important for BA homeostasis, whereas DCA and CA were intermediate, LCA the least, and UDCA ineffective.
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