Heterogeneous expression of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.

Twisk, Jaap; Hoekman, Marco F.M.; Mager, Willem H.; Moorman, Antoon F.M.; Boer, P. A. J. De; Scheja, Ludger; Princen, H.M.G.; Gebhardt, Rolf

doi:10.1172/jci117773

Cited by 65 publications

(61 citation statements)

References 57 publications

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“…When elobixibat was taken before breakfast, plasma C4 level was raised while the C max and AUC were declined compared with fasting. This result indicates that BA synthesis was upregulated by food intake as well as due to interruption of enterohepatic circulation 12, 22 by elobixibat. However, we did not observe a major difference in the incidence of GI‐related AEs between regimens.…”

Section: Discussionmentioning

confidence: 85%

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

Kumagai

Aoki

Sasaki

et al. 2018

Brit J Clinical Pharma

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AimsElobixibat is a minimally absorbed ileal bile acid transporter inhibitor. This study aimed to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of elobixibat in Japanese patients with chronic constipation.MethodsThis study consisted of single‐dose and multiple‐dose tests with a dose‐escalating design. Sixty patients including females and males were randomized into five dose levels of elobixibat (2.5, 5, 10, 15 or 20 mg, n = 10 per level) and corresponding placebo (n = 2 per group). A crossover design was used to examine food effect in single‐dose test. Patients received test tablets once daily for 14 days in multiple‐dose test. We assessed pharmacokinetic‐dose proportionality, levels of serum high‐ and low‐density lipoprotein cholesterol and plasma 7α‐hydroxy‐4‐cholesten‐3‐one (C4), food effect and sex‐specific effect. Adverse events and bowel functions such as bowel movements, stool consistency and straining were also evaluated.ResultsFood consumption reduced systemic exposure by around 80% [e.g. least squares mean (ratio of breakfast/no breakfast) maximum plasma concentration: 0.2085 (90% confidence interval, 0.1371–0.3172) at 15 mg] while increased plasma C4 level (P < 0.001). In the multiple‐dose test, elobixibat reduced low‐density lipoprotein cholesterol and increased C4 whilst unaltering high‐density lipoprotein cholesterol level. The increased spontaneous bowel movement frequency was correlated with higher dosage and higher C4 level (R2 = 0.5929 at Week 2). Adverse events were mainly gastrointestinal symptoms, most of which were mild.ConclusionsElobixibat should be taken before breakfast. Once‐daily administration of elobixibat was found to be safe and tolerated up to 20 mg in female and male patients with chronic constipation.

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Section: Discussionmentioning

confidence: 85%

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

Kumagai

Aoki

Sasaki

et al. 2018

Brit J Clinical Pharma

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“…Hepatic lipogenic enzymes appear to have a more perivenous distribution (32,33), whereas the rate-limiting step in bile acid synthesis, cholesterol 7␣-hydroxylase, is found mainly in periportal hepatocytes (34). Expression of hBACS was also found to have a more periportal distribution.…”

Section: Discussionmentioning

confidence: 94%

Participation of Two Members of the Very Long-chain Acyl-CoA Synthetase Family in Bile Acid Synthesis and Recycling

Mihalik¹,

Steinberg²,

Pei³

et al. 2002

Journal of Biological Chemistry

105

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275, 15605-15608). We now show that this enzyme also activates chenodeoxycholate, the secondary bile acids deoxycholate and lithocholate, and 3␣,7␣,12␣-trihydroxy-5␤-cholestanoic acid. In contrast, VLCS activated 3␣,7␣,12␣-trihydroxy-5␤-cholestanoate, but did not utilize any of the C 24 bile acids as substrates. We hypothesize that the primary function of homolog 2 is in the reactivation and recycling of C 24 bile acids, whereas VLCS participates in the de novo synthesis pathway. Results of in situ hybridization, topographic orientation, and inhibition studies are consistent with the proposed roles of these enzymes in bile acid metabolism.

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“…Our studies in healthy volunteers 19 clearly support such an assumption, although a reduced capability of conjugated cholate uptake in HepG2 cells 15 may have contributed to these observations in this experimental system. With respect to de novo cholesterol in the short term, bile acid uptake by periportal hepatocytes, known for their high capacity to synthesize cholesterol 65 and cholate, 66 may have stimulated cholate formation from de novo cholesterol by increasing the availability of newly formed cholesterol. This is based on the assumption that a stimulation of cholesterol synthesis is unlikely under these conditions.…”

Section: Discussionmentioning

confidence: 99%

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

et al. 1999

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Hepatic bile acid synthesis is regulated by recirculating bile acids, possibly by modulating the availability of newly synthesized and preformed cholesterol. Because data in the hamster on this mechanism are lacking, we fitted these animals with an extracorporeal bile duct and administered tritiated water intraperitoneally to label newly formed cholesterol. After interruption of the enterohepatic circulation, physiological and double-physiological doses of conjugated cholate (25 or 50 mol/100 g · h) or of unconjugated deoxycholate (6 or 12 mol) were infused intraduodenally for 54 hours and compared with controls. De novo and preformed cholesterol directly secreted into bile or used for cholate and chenodeoxycholate synthesis were quantitated by high-pressure liquid chromatography (HPLC)-liquid scintillation. Directly after depletion of the bile acid pool (6-9 hours) at nearly physiological conditions, chenodeoxycholate synthesis was significantly reduced by cholate and deoxycholate by up to 45% to 51%, whereas cholate formation decreased by Ϸ22% during deoxycholate. This short-term effect was mainly mediated by reduced synthesis from preformed cholesterol. After long-term bile depletion (30-54 hours), bile acid synthesis returned to control levels during 25 mol of cholate and of both deoxycholate doses. In contrast, only 50 mol of cholate prevented derepression of bile acid synthesis. This long-term effect was mainly attributed to a diminished formation from de novo cholesterol exceeding the reduced synthesis from preformed cholesterol. In summary, short-and long-term regulation of bile acid synthesis in hamsters differs with respect to availabilities of preformed and de novo cholesterol. (HEPATOL-OGY 1999;30:230-237.)

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Heterogeneous expression of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase genes in the rat liver lobulus.

Cited by 65 publications

References 57 publications

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

Effect of single and multiple doses of elobixibat, an ileal bile acid transporter inhibitor, on chronic constipation: A randomized controlled trial

Participation of Two Members of the Very Long-chain Acyl-CoA Synthetase Family in Bile Acid Synthesis and Recycling

Complex feedback regulation of bile acid synthesis in the hamster: The role of newly synthesized cholesterol

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