Differences in the Regulation of the Classical and the Alternative Pathway for Bile Acid Synthesis in Human Liver

According to current views, the second peroxisomal β-oxidation pathway is responsible for the degradation of the side chain of bile acid intermediates. Peroxisomal multifunctional enzyme type 2 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(R)-3-hydroxyacyl-CoA dehydrogenase; MFE-2] catalyses the second (hydration) and third (dehydrogenation) reactions of the pathway. Deficiency of MFE-2 leads to accumulation of very-long-chain fatty acids, 2-methyl-branched fatty acids and C27 bile acid intermediates in plasma, but bile acid synthesis is not blocked completely. In this study we describe an alternative pathway, which allows MFE-2 deficiency to be overcome. The alternative pathway consists of α-methylacyl-CoA racemase and peroxisomal multifunctional enzyme type 1 [peroxisomal multifunctional 2-enoyl-CoA hydratase/(S)-3-hydroxyacyl-CoA dehydrogenase; MFE-1]. (24E)-3α,7α,12α-Trihydroxy-5β-cholest-24-enoyl-CoA, the presumed physiological isomer, is hydrated by MFE-1 with the formation of (24S,25S)-3α,7α,12α,24-tetrahydroxy-5β-cholestanoyl-CoA [(24S,25S)-24-OH-THCA-CoA], which after conversion by a α-methylacyl-CoA racemase into the (24S,25R) isomer can again be dehydrogenated by MFE-1 to 24-keto-3α,7α,12α-trihydroxycholestanoyl-CoA, a physiological intermediate in cholic acid synthesis. The discovery of the alternative pathway of cholesterol side-chain oxidation will improve diagnosis of peroxisomal deficiencies by identification of serum 24-OH-THCA-CoA diastereomer profiles.

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Human liver cholesteryl ester hydrolase: cloning, molecular characterization, and role in cellular cholesterol homeostasis

Physiological Genomics ◽

10.1152/physiolgenomics.00187.2005 ◽

2005 ◽

Vol 23 (3) ◽

pp. 304-310 ◽

Cited By ~ 47

Author(s):

Bin Zhao ◽

Ramesh Natarajan ◽

Shobha Ghosh

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Human Liver ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Human Hepatocytes ◽

Cholesterol Homeostasis ◽

Cholesteryl Esters ◽

Ester Hydrolase ◽

Hydrolysis Of

The liver regulates cholesterol homeostasis and eliminates excess cholesterol as bile acids or biliary cholesterol. Free cholesterol for bile acid synthesis or biliary secretion is obtained by the hydrolysis of stored cholesteryl esters or from cholesteryl esters taken up by the liver from high-density lipoproteins via a selective uptake pathway. The present study was undertaken to characterize the enzyme catalyzing this reaction, namely, cholesterol ester hydrolase (CEH) from the human liver, and demonstrate its role in regulating bile acid synthesis. Two cDNAs were isolated from the human liver that differed only in the presence of an additional alanine at position 18 in one of the clones. Transient transfection of COS-7 cells with a eukaryotic expression vector containing either of these two cDNAs resulted in significant increase in the hydrolysis of cholesteryl esters, authenticating these clones as human liver CEH. CEH mRNA and protein expression in human hepatocytes were demonstrated by real-time PCR and Western blot analyses, respectively, confirming the location of this enzyme in the cell type involved in hepatic cholesterol homeostasis. Overexpression of these CEH clones in human hepatocytes resulted in significant increase in bile acid synthesis, demonstrating a role for liver CEH in modulating bile acid synthesis. This CEH gene mapped on human chromosome 16, and the two clones represent two different transcript variants resulting from splice shifts at exon 1. In conclusion, these data identify that human liver CEH was expressed in hepatocytes, where it potentially regulates the synthesis of bile acids and thus the removal of cholesterol from the body.

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Hepatic bile acid metabolism in the neonatal hamster: expansion of the bile acid pool parallels increased Cyp7a1 expression levels

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90515.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. G144-G151 ◽

Cited By ~ 4

Author(s):

Katie T. Burke ◽

Paul S. Horn ◽

Patrick Tso ◽

James E. Heubi ◽

Laura A. Woollett

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Alternative Pathway ◽

Newborn Infants ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Bile Acid Metabolism ◽

Mrna Levels ◽

Bile Acid Pool ◽

Acid Pool

Intraluminal concentrations of bile acids are low in newborn infants and increase rapidly after birth, at least partly owing to increased bile acid synthesis rates. The expansion of the bile acid pool is critical since bile acids are required to stimulate bile flow and absorb lipids, a major component of newborn diets. The purpose of the present studies was to determine the mechanism responsible for the increase in bile acid synthesis rates and the subsequent enlargement of bile acid pool sizes (BAPS) during the neonatal period, and how changes in circulating hormone levels might affect BAPS. In the hamster, pool size was low just after birth and increased modestly until 10.5 days postpartum (dpp). BAPS increased more significantly (∼3-fold) between 10.5 and 15.5 dpp. An increase in mRNA and protein levels of cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting step in classical bile acid synthesis, immediately preceded an increase in BAPS. In contrast, levels of oxysterol 7α-hydroxylase (Cyp7b1), a key enzyme in bile acid synthesis by the alternative pathway, were relatively elevated by 1.5 dpp. farnesyl X receptor (FXR) and short heterodimeric partner (SHP) mRNA levels remained relatively constant at a time when Cyp7a1 levels increased. Finally, although simultaneous increases in circulating cortisol and Cyp7a1 levels occurred, precocious expression of Cyp7a1 could not be induced in neonatal hamsters with dexamethasone. Thus the significant increase in Cyp7a1 levels in neonatal hamsters is due to mechanisms independent of the FXR and SHP pathway and cortisol.

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The acidic pathway of bile acid synthesis: Not just an alternative pathway

Liver Research ◽

10.1016/j.livres.2019.05.001 ◽

2019 ◽

Vol 3 (2) ◽

pp. 88-98 ◽

Cited By ~ 16

Author(s):

William M. Pandak ◽

Genta Kakiyama

Keyword(s):

Bile Acid ◽

Alternative Pathway ◽

Acid Synthesis ◽

Bile Acid Synthesis

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Tissue-specific Mechanisms of Bile Acid Homeostasis and Activation of FXR-FGF19 Signaling in Preterm and Term Neonatal Pigs

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00274.2021 ◽

2021 ◽

Author(s):

Caitlin Vonderohe ◽

Gregory Guthrie ◽

Barbara Stoll ◽

Shaji Chacko ◽

Harry Dawson ◽

...

Keyword(s):

Bile Acid ◽

Gestational Age ◽

Molecular Mechanisms ◽

Alternative Pathway ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Tissue Specific ◽

Neonatal Pigs ◽

Bile Acid Pool Size ◽

Ileal Tissue

Background & Aims: The tissue specific molecular mechanisms involved in perinatal liver and intestinal FXR-FGF19 signaling are poorly defined. Our aim was to establish how gestational age and feeding status affect bile acid synthesis pathway, bile acid pool size, ileal response to bile acid stimulation, genes involved in bile acid-FXR-FGF19 signaling and plasma FGF19 in neonatal pigs. Methods Term (n=23) and preterm (n=33) pigs were born via cesarean section at 100% and 90% gestation, respectively. Plasma FGF19, hepatic bile acid and oxysterol profiles, and FXR target gene expression was assessed in pigs at birth and after a bolus feed on day 3 of life. Pig ileal tissue explants were used to measure signaling response to bile acids. Results Preterm pigs had smaller, more hydrophobic bile acid pools, lower plasma FGF19, and blunted FXR-mediated ileal response to bile acid stimulation than term pigs. GATA-4 expression was higher in jejunum than ileum, and was higher in preterm than term pig ileum. Hepatic oxysterol analysis suggested dominance of the alternative pathway of bile acid synthesis in neonates, regardless of gestational age and persists in preterm pigs after feeding on day 3. Conclusion These results highlight the tissue-specific molecular basis for the immature enterohepatic bile acid signaling via FXR-FGF19 in preterm pigs and may have implications for disturbances of bile acid homeostasis and metabolism in preterm infants.

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Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

Biochemical Journal ◽

10.1042/bj2750501 ◽

1991 ◽

Vol 275 (2) ◽

pp. 501-505 ◽

Cited By ~ 75

Author(s):

H M Princen ◽

P Meijer ◽

B G Wolthers ◽

R J Vonk ◽

F Kuipers

Keyword(s):

Bile Acid ◽

Cyclosporin A ◽

Bile Acids ◽

Chenodeoxycholic Acid ◽

Alternative Pathway ◽

Rat Hepatocytes ◽

Acid Synthesis ◽

Liver Mitochondria ◽

Bile Acid Synthesis ◽

Rat Liver Mitochondria

Bile acid synthesis, determined by conversion of [4-14C]cholesterol into bile acids in rat and human hepatocytes and by measurement of mass production of bile acids in rat hepatocytes, was dose-dependently decreased by cyclosporin A, with 52% (rat) and 45% (human) inhibition of 10 microM. The decreased bile acid production in rat hepatocytes was due only to a fall in the synthesis of beta-muricholic and chenodeoxycholic acids (-64% at 10 microM-cyclosporin A), with no change in the formation of cholic acid. In isolated rat liver mitochondria, 26-hydroxylation of cholesterol was potently inhibited by the drug (concn. giving half-maximal inhibition = 4 microM). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.

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