Bioconversion of 3β-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

Mano, Nariyasu; Sato, Yoshiaki; Nagata, Masanori; Goto, Takaaki; Goto, Junichi

doi:10.1194/jlr.m400157-jlr200

Cited by 23 publications

(20 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, ␣␤␥ENaC is expressed in human and mouse cholangiocytes (56), indicating that bile acids may be physiologically relevant modulators of ENaC function in bile ducts. Moreover, ␦ENaC is expressed abundantly in different brain regions (26, 27, 57), and CDCA may also be accumulated or locally produced in the brain (58). Thus, it is conceivable that CDCA can affect ␦␤␥ENaC in the brain.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site

Ilyaskin¹,

Diakov²,

Korbmacher

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The epithelial sodium channel (ENaC) is a member of the ENaC/degenerin ion channel family, which also includes the bile acid-sensitive ion channel (BASIC). So far little is known about the effects of bile acids on ENaC function. ENaC is probably a heterotrimer consisting of three well characterized subunits (␣␤␥). In humans, but not in mice and rats, an additional ␦-subunit exists. The aim of this study was to investigate the effects of chenodeoxycholic, cholic, and deoxycholic acid in unconjugated (CDCA, CA, and DCA) and tauro-conjugated (t-CDCA, t-CA, t-DCA) form on human ENaC in its ␣␤␥-and ␦␤␥-configuration. We demonstrated that tauro-conjugated bile acids significantly stimulate ENaC in the ␣␤␥-and in the ␦␤␥-configuration. In contrast, non-conjugated bile acids have a robust stimulatory effect only on ␦␤␥ENaC. Bile acids stimulate ENaC-mediated currents by increasing the open probability of active channels without recruiting additional near-silent channels known to be activated by proteases. Stimulation of ENaC activity by bile acids is accompanied by a significant reduction of the single-channel current amplitude, indicating an interaction of bile acids with a region close to the channel pore. Analysis of the known ASIC1 (acid-sensing ion channel) crystal structure suggested that bile acids may bind to the pore region at the degenerin site of ENaC. Substitution of a single amino acid residue within the degenerin region of ␤ENaC (N521C or N521A) significantly reduced the stimulatory effect of bile acids on ENaC, suggesting that this site is critical for the functional interaction of bile acids with the channel.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site

Ilyaskin¹,

Diakov²,

Korbmacher

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Under in vitro conditions, there is little or no metabolism of 24S-hydroxycholesterol in various preparations from neurological tissues, whereas highly efficient systems exist for conversion of 27-hydroxycholesterol into more polar products. These include 7 ␣ ,27-dihydroxycholesterol, 7 ␣ -hydroxy-3-oxo-4-cholestenoic acid, and perhaps also chenodeoxycholic acid (21)(22)(23). However, to what extent this occurs under in vivo conditions, and how the different metabolites may be removed from the brain, are unknown at present.…”

Section: Discussionmentioning

confidence: 99%

Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain

Heverin

Meaney

Lütjohann

et al. 2005

Journal of Lipid Research

231

228

View full text Add to dashboard Cite

Side chain oxidized oxysterols have a unique ability to traverse lipophilic membranes. We tested the hypothesis that there is a net flux of 27-hydroxycholesterol from the circulation into the brain using plasma samples collected from the internal jugular vein and an artery of healthy male volunteers. Two independent studies were performed, one in which total levels of 27-hydroxycholesterol were measured and one in which the free fraction of 27-hydroxycholesterol was measured. In the majority of subjects studied, the level of 27-hydroxycholesterol was higher in the artery than in the vein, and uptake from the circulation was calculated to be about 5 mg/24 h. The distribution of 27-hydroxycholesterol in human brain was found to be consistent with an extracerebral origin, with a concentration gradient from the white to the gray matter-a situation opposite that of 24S-hydroxycholesterol, which is exclusively formed in brain. In view of the fact that the blood-brain barrier is impermeable to cholesterol and that 27-hydroxycholesterol is a potent regulator of several cholesterol-sensitive genes, the flux of 27-hydroxycholesterol into the brain may be an important link between intraand extracerebral cholesterol homeostasis.

show abstract

“…9,10) In addition, 5-cholenoic acid has a wider β-side of the steroid skeleton than 5β-cholanoic acid, indicating that its retention time is more likely to be a ected by the positions of hydroxy groups on the steroid skeleton. 11) erefore, we speculated the compound observed at m/z 469 included a hydroxy group at the C-7β position.…”

Section: Resultsmentioning

confidence: 99%

Identification of Two Sulfated Cholesterol Metabolites Found in the Urine of a Patient with Niemann–Pick Disease Type C as Novel Candidate Diagnostic Markers

et al. 2016

Self Cite

View full text Add to dashboard Cite

In the urine of a Niemann-Pick disease type C (NPC) patient, we have identi ed three characteristic intense peaks that have not been observed in the urine of a 3β-hydroxysteroid-Δ 5 -C 27 -steroid dehydrogenase de ciency patient or a healthy infant and adult. Based on accurate masses of the protonated molecules, we focused on two of them as candidate NPC diagnostic markers. Two synthesized authentic preparations agreed with the two compounds found in NPC patient urine in regard to both chromatographic behavior and accurate masses of the deprotonated molecules. Moreover, the isotopic patterns of the deprotonated molecules, twin peaks unique to the sulfur-containing compounds appearing in their second isotope positions, and accurate masses of product ions observed at m/z 97 also agreed between the target compounds and authentic preparations. We identi ed the two compounds as the sulfated cholesterol metabolites as 3β-sulfooxy-7β-hydroxy-5-cholen-24-oic acid and 3β-sulfooxy-7-oxo-5-cholen-24-oic acid.ese two compounds represent more promising candidate diagnostic markers for NPC diagnosis than three other candidates that are multiple conjugates of cholesterol metabolites, 3β-sulfooxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid and its glycine and taurine conjugates, although we have reported an analytical method for determining the urinary levels of these compounds using liquid chromatography/electrospray ionization tandem mass spectrometry, because of their lack of N-acetylglucosamine conjugation.

show abstract

Bioconversion of 3β-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

Cited by 23 publications

References 35 publications

Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site

Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site

Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain

Identification of Two Sulfated Cholesterol Metabolites Found in the Urine of a Patient with Niemann–Pick Disease Type C as Novel Candidate Diagnostic Markers

Contact Info

Product

Resources

About