Unconjugated bile acids in rat brain: Analytical method based on LC/ESI-MS/MS with chemical derivatization and estimation of their origin by comparison to serum levels

Higashi, Tatsuya; Watanabe, Shuichi; Tomaru, Koki; Yamazaki, Wataru; Yoshizawa, Kazumi; Ogawa, Shoujiro; Nagao, Hidenori; Minato, Kouichi; Maekawa, Masamitsu; Mano, Nariyasu

doi:10.1016/j.steroids.2017.07.001

Cited by 70 publications

(72 citation statements)

References 26 publications

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“…Its role in human physiology is still unclear, however . Another interesting speculation relates to that unconjugated BAs seem to cross the blood–brain barrier, and have been detected in the central nervous system of animals . In fact, in vitro studies indicate that BAs may influence the hypothalamic‐pituitary‐adrenal axis influencing diurnal rhythms , and BA‐mediated effects have also been proposed in the pathogenesis of hepatic encephalopathy .…”

Section: Discussionmentioning

confidence: 99%

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism

Al-Khaifi

Straniero

Voronova³

et al. 2018

J Intern Med

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Section: Discussionmentioning

confidence: 99%

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism

Al-Khaifi

Straniero

Voronova³

et al. 2018

J Intern Med

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“…Cell lines, animal models, and human studies suggest that levels of such BA, particularly DCA, lead to a disruption of mitochondrial membranes resulting in increased reactive oxygen species, markers of inflammation, and apoptosis as well as decreases in cell viability and DNA synthesis [34,35,78]. DCA increases BBB permeability with deuterium labelled DCA showing it crosses the BBB in rodents [27,29]. Increased amounts of secondary BAs in blood may enter the brain through induced permeability of the BBB, affecting brain physiology and metabolism [28].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the BA nuclear receptor FXR, TGR5, and transporters Ostα/Ostβ seem to be expressed in the brain [79]. Several studies in human and animal brains also revealed that the full panel of BAs are found in the brain [24][25][26][27], but it is unclear whether this is due to transport from the periphery, from local synthesis, or both. The function of these BAs in the brain remains poorly defined with some support for them acting as neurosteroids [80] BA levels and the gut microbiome influence each other, where BSH-rich bacteria readily modify the BA profile while, on the other hand, intestinal BAs control the growth and maintenance of commensal bacteria, maintain barrier integrity, and modulate the immune system [81][82][83][84].…”

Section: Discussionmentioning

confidence: 99%

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Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

MahmoudianDehkordi

Arnold

Nho

et al. 2018

Preprint

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IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).MethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.ResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.ConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.

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“…1) is a derivatization reagent developed in our laboratories for the sensitive LC/ESI-MS/MS assays of carboxylic acids. 8 This reagent has a high reactivity and applicability for various carboxylic acids, including fatty acids, 8 bile acids, 9 and steroid glucuronides. 10 It is expected that the DAPPZ isotopologues will allow the analysis of a carboxylic acid in multiple samples in a single LC/ESI-MS/MS run.…”

Section: Introductionmentioning

confidence: 99%

Enhancing LC/ESI-MS/MS Throughput for Plasma Bile Acid Assay by Derivatization-based Sample-Multiplexing

Koyagi

Hobo

et al. 2020

ANAL. SCI.

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Liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) enables the accurate and precise quantification of various analytes at very low concentrations, but it has room for improvement in analysis throughput. Multiplexing of samples in the same injection could be a promising procedure for enhancing the analysis throughput. This could be achieved by derivatization of the multiple samples with multiple isotopologous reagents. In this study, a sample-multiplexed LC/ESI-MS/MS assay using the 1-[(4-dimethylaminophenyl)carbonyl]piperazine (DAPPZ) isotopologues (2 H0-, 2 H3-and 2 H6-forms) was developed and validated for the simultaneous determination of primary bile acids in three different plasma samples in a single run. The developed method had satisfactory intra-and inter-assay precisions (≤ 2.3% and ≤ 4.2%, respectively) and accuracy (99.0-100.3%), and could reduce the total LC/ESI-MS/MS run time by more than 60% for 42 samples compared to the conventional method. Thus, the derivatization with the DAPPZ isotopologues worked well for enhancing the throughput of the LC/ESI-MS/MS assay of the bile acids.

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Unconjugated bile acids in rat brain: Analytical method based on LC/ESI-MS/MS with chemical derivatization and estimation of their origin by comparison to serum levels

Cited by 70 publications

References 26 publications

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

Enhancing LC/ESI-MS/MS Throughput for Plasma Bile Acid Assay by Derivatization-based Sample-Multiplexing

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