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

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.

scholarly journals Recent advances in understanding bile acid homeostasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2029 ◽  
Author(s):  
John YL Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Recent Advances ◽  
Bile Acid Pool Size ◽  
Bile Acid Receptor ◽  
Acid Toxicity ◽  
G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

scholarly journals Transport of Cholesterol into Mitochondria Is Rate-limiting for Bile Acid Synthesis via the Alternative Pathway in Primary Rat Hepatocytes

2002 ◽  
Vol 277 (50) ◽  
pp. 48158-48164 ◽  
Author(s):  
William M. Pandak ◽  
Shunlin Ren ◽  
Dalila Marques ◽  
Elizabeth Hall ◽  
Kaye Redford ◽  
...  
Keyword(s):  
Bile Acid ◽  
Alternative Pathway ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Primary Rat Hepatocytes ◽  
Rate Limiting

scholarly journals Biogeography of microbial bile acid transformations along the murine gut

2020 ◽  
Vol 61 (11) ◽  
pp. 1450-1463 ◽  
Author(s):  
Solenne Marion ◽  
Lyne Desharnais ◽  
Nicolas Studer ◽  
Yuan Dong ◽  
Matheus D. Notter ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Bile Acid Pool Size ◽  
Host Signaling ◽  
Gut Microorganisms ◽  
Gut Microbial Community

Bile acids, which are synthesized from cholesterol by the liver, are chemically transformed along the intestinal tract by the gut microbiota, and the products of these transformations signal through host receptors, affecting overall host health. These transformations include bile acid deconjugation, oxidation, and 7α-dehydroxylation. An understanding of the biogeography of bile acid transformations in the gut is critical because deconjugation is a prerequisite for 7α-dehydroxylation and because most gut microorganisms harbor bile acid transformation capacity. Here, we used a coupled metabolomic and metaproteomic approach to probe in vivo activity of the gut microbial community in a gnotobiotic mouse model. Results revealed the involvement of Clostridium scindens in 7α-dehydroxylation, of the genera Muribaculum and Bacteroides in deconjugation, and of six additional organisms in oxidation (the genera Clostridium, Muribaculum, Bacteroides, Bifidobacterium, Acutalibacter, and Akkermansia). Furthermore, the bile acid profile in mice with a more complex microbiota, a dysbiosed microbiota, or no microbiota was considered. For instance, conventional mice harbor a large diversity of bile acids, but treatment with an antibiotic such as clindamycin results in the complete inhibition of 7α-dehydroxylation, underscoring the strong inhibition of organisms that are capable of carrying out this process by this compound. Finally, a comparison of the hepatic bile acid pool size as a function of microbiota revealed that a reduced microbiota affects host signaling but not necessarily bile acid synthesis. In this study, bile acid transformations were mapped to the associated active microorganisms, offering a systematic characterization of the relationship between microbiota and bile acid composition.

scholarly journals Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice

Hepatology ◽  
2012 ◽  
Vol 56 (3) ◽  
pp. 1034-1043 ◽  
Author(s):  
Bo Kong ◽  
Li Wang ◽  
John Y.L. Chiang ◽  
Youcai Zhang ◽  
Curtis D. Klaassen ◽  
...  
Keyword(s):  
Bile Acid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Tissue Specific ◽  
Expression Of Genes

The role of α-methylacyl-CoA racemase in bile acid synthesis

2002 ◽  
Vol 363 (3) ◽  
pp. 801-807 ◽  
Author(s):  
Dean A. CUEBAS ◽  
Christopher PHILLIPS ◽  
Werner SCHMITZ ◽  
Ernst CONZELMANN ◽  
Dmitry K. NOVIKOV
Keyword(s):  
Fatty Acids ◽  
Bile Acid ◽  
Alternative Pathway ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Side Chain ◽  
Multifunctional Enzyme ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Dehydrogenation Reactions ◽  
Enoyl Coa Hydratase

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.

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

2009 ◽  
Vol 297 (1) ◽  
pp. G144-G151 ◽  
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.

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

2002 ◽  
Vol 277 (30) ◽  
pp. 26804-26807 ◽  
Author(s):  
Ingemar Björkhem ◽  
Zufan Araya ◽  
Mats Rudling ◽  
Bo Angelin ◽  
Curt Einarsson ◽  
...  
Keyword(s):  
Bile Acid ◽  
Human Liver ◽  
Alternative Pathway ◽  
Acid Synthesis ◽  
Bile Acid Synthesis

Sterol 27-hydroxylase is a tissue specific regulator of cholesterol and bile acid synthesis

2000 ◽  
Vol 118 (4) ◽  
pp. A999 ◽  
Author(s):  
Elizabeth A. Hall ◽  
Zdravko R. Vlahcevic ◽  
Phillip B. Hylemon ◽  
Darrell Mallonee ◽  
William M. Pandak
Keyword(s):  
Bile Acid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Tissue Specific

Regulation of genes related to cholesterol metabolism in rainbow trout (Oncorhynchus mykiss) fed a plant-based diet

2018 ◽  
Vol 314 (1) ◽  
pp. R58-R70 ◽  
Author(s):  
Tengfei Zhu ◽  
Geneviève Corraze ◽  
Elisabeth Plagnes-Juan ◽  
Edwige Quillet ◽  
Mathilde Dupont-Nivet ◽  
...  
Keyword(s):  
Rainbow Trout ◽  
Bile Acid ◽  
Cholesterol Efflux ◽  
Cholesterol Synthesis ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Expression Of Genes ◽  
Nutritional Characteristics

When compared with fish meal and fish oil, plant ingredients differ not only in their protein content and amino acid and fatty acid profiles but are also devoid of cholesterol, the major component of cell membrane and precursor of several bioactive compounds. Based on these nutritional characteristics, plant-based diets can affect fish physiology and cholesterol metabolism. To investigate the mechanisms underlying cholesterol homeostasis, rainbow trout were fed from 1 g body wt for 6 mo with a totally plant-based diet (V), a marine diet (M), and a marine-restricted diet (MR), with feed intake adjusted to that of the V group. The expression of genes involved in cholesterol synthesis, esterification, excretion, bile acid synthesis, and cholesterol efflux was measured in liver. Results showed that genes involved in cholesterol synthesis were upregulated in trout fed the V diet, whereas expression of genes related to bile acid synthesis ( cyp7a1) and cholesterol elimination ( abcg8) were reduced. Feeding trout the V diet also enhanced the expression of srebp-2 while reducing that of lxrα and miR-223. Overall, these data suggested that rainbow trout coped with the altered nutritional characteristics and absence of dietary cholesterol supply by increasing cholesterol synthesis and limiting cholesterol efflux through molecular mechanisms involving at least srebp-2, lxrα, and miR-223. However, plasma and body cholesterol levels in trout fed the V diet were lower than in fish fed the M diet, raising the question of the role of cholesterol in the negative effect of plant-based diet on growth.

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