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Dicks L, Schuh-von Graevenitz K, Prehn C, Sadri H, Murani E, Hosseini Ghaffari M, Häussler S. Bile acid profiles and mRNA abundance of bile acid-related genes in adipose tissue of dairy cows with high versus normal body condition. J Dairy Sci 2024; 107:6288-6307. [PMID: 38490538 DOI: 10.3168/jds.2024-24346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/14/2024] [Indexed: 03/17/2024]
Abstract
Besides their lipid-digestive role, bile acids (BA) influence overall energy homeostasis, such as glucose and lipid metabolism. We hypothesized that BA along with their receptors, regulatory enzymes, and transporters are present in subcutaneous adipose tissue (scAT). In addition, we hypothesized that their mRNA abundance varies with the body condition of dairy cows around calving. Therefore, we analyzed BA in serum and scAT as well as the mRNA abundance of BA-related enzymes, transporters, and receptors in scAT during the transition period in cows with different body conditions around calving. In a previously established animal model, 38 German Holstein cows were divided into either a high (HBCS; n = 19) or normal BCS (NBCS; n = 19) group based on their BCS and back-fat thickness (BFT). Cows were fed different diets to achieve the targeted differences in BCS and BFT (NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off at 7 wk antepartum. During the dry period and subsequent lactation, both groups were fed the same diets according to their energy demands. Using a targeted metabolomics approach via liquid chromatography-electrospray ionization-MS /MS, BA were analyzed in serum and scAT at wk -7, 1, 3, and 12 relative to parturition. In serum, 15 BA were observed: cholic acid (CA), chenodeoxycholic acid (CDCA), glycocholic acid (GCA), taurocholic acid (TCA), glycochenodeoxycholic acid (GCDCA), taurochenodeoxycholic acid, deoxycholic acid (DCA), lithocholic acid, glycodeoxycholic acid (GDCA), glycolithocholic acid, taurodeoxycholic acid, taurolithocholic acid, β-muricholic acid, tauromuricholic acid (sum of α and β), and glycoursodeoxycholic acid, whereas in scAT 7 BA were detected: CA, GCA, TCA, GCDCA, taurochenodeoxycholic acid, GDCA, and taurodeoxycholic acid. In serum and scAT samples, the primary BA CA and its conjugate GCA were predominantly detected. Increasing serum concentrations of CA, CDCA, TCA, GCA, GCDCA, DCA, and β-muricholic acid with the onset of lactation might be related to the increasing DMI after parturition. Furthermore, serum concentrations of CA, CDCA, GCA, DCA, GCDCA, TCA, lithocholic acid, and GDCA were lower in HBCS cows compared with NBCS cows, concomitant with increased lipolysis in HBCS cows. The correlation between CA in serum and scAT may point to the transport of CA across cell membranes. Overall, the findings of the present study suggest a potential role of BA in lipid metabolism depending on the body condition of periparturient dairy cows.
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Affiliation(s)
- Lena Dicks
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany
| | - Katharina Schuh-von Graevenitz
- Department of Life Sciences and Engineering, Animal Nutrition and Hygiene Unit, University of Applied Sciences Bingen, 55411 Bingen am Rhein, Germany
| | - Cornelia Prehn
- Helmholtz Zentrum München, German Research Center for Environmental Health, Metabolomics and Proteomics Core, 85764 Neuherberg, Germany
| | - Hassan Sadri
- Department of Clinical Science, Faculty of Veterinary Medicine, University of Tabriz, 516616471 Tabriz, Iran
| | - Eduard Murani
- Research Institute for Farm Animal Biology (FBN), Institute for Genome Biology, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany
| | | | - Susanne Häussler
- Institute of Animal Science, Physiology Unit, University of Bonn, 53115 Bonn, Germany.
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Nishino T, Takahashi K, Tomori S, Ono S, Mimaki M. Effects of diurnal variation of bile acids by meal on cyclosporine A absorption. Pediatr Int 2022; 64:e15296. [PMID: 36421923 DOI: 10.1111/ped.15296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 06/10/2022] [Accepted: 07/08/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Stabilizing blood levels with microemulsified cyclosporine A (CsA), administered in many pediatric kidney diseases, is important for effective immunosuppression and reduced nephrotoxicity. CsA is affected by total bile acids (TBAs); however, no reports have simultaneously measured both. We aimed to elucidate the hypothesized relationship between TBA levels and diurnal variation in CsA in children. METHODS We retrospectively reviewed the medical records of children who were taking oral CsA for the treatment of kidney diseases between January 2016 and July 2021. They consumed four balanced meals and snacks during the day. CsA and TBA were measured twice, in pairs, before and at 0.5, 1, 1.5, 2, 3, and 4 h after oral administration in the morning and evening, and the four-h area under curve (AUC)0-4 of CsA and trough-to-peak ratio (TPR) of TBA were compared. RESULTS Fifty-eight pairs were measured in total; 12 children had idiopathic nephrotic syndrome and 4 children had immunoglobulin A vasculitis with nephritis. The median age at measurement was 7.5 years and the dose of CsA was 3.8 mg/kg/day. The AUC0-4 (ng·h/mL) was significantly lower in the evening than in the morning (1,669 vs. 1,451, P < 0.001). The TPR of TBA was significantly higher in the evening than in the morning (0.14 vs. 0.25, P < 0.001). CONCLUSIONS The low AUC0-4 and slow TBA secretion observed in the evening may be due to pediatric-specific dietary rhythms; thus, snack timing should be considered in children for stabilizing CsA levels.
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Affiliation(s)
- Tomohiko Nishino
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Kazuhiro Takahashi
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Shinya Tomori
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Sayaka Ono
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Masakazu Mimaki
- Department of Pediatrics, Teikyo University School of Medicine, Itabashi-ku, Tokyo, Japan
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Qi L, Tian Y, Chen Y. Circulating Bile Acid Profiles: A Need for Further Examination. J Clin Endocrinol Metab 2021; 106:3093-3112. [PMID: 34279029 DOI: 10.1210/clinem/dgab531] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Indexed: 12/15/2022]
Abstract
CONTEXT Bile acids (BAs) are increasingly recognized as metabolic and chronobiologic integrators that synchronize the systemic metabolic response to nutrient availability. Alterations in the concentration and/or composition of circulating BAs are associated with a number of metabolic disorders, such as obesity, type 2 diabetes mellitus (T2DM), insulin resistance (IR), and metabolic associated fatty liver disease (MAFLD). This review summarizes recent evidence that links abnormal circulating BA profiles to multiple metabolic disorders, and discusses the possible mechanisms underlying the connections to determine the role of BA profiling as a novel biomarker for these abnormalities. EVIDENCE ACQUISITION The review is based on a collection of primary and review literature gathered from a PubMed search of BAs, T2DM, IR, and MAFLD, among other keywords. EVIDENCE SYNTHESIS Obese and IR subjects appear to have elevated fasting circulating BAs but lower postprandial increase when compared with controls. The possible underlying mechanisms are disruption in the synchronization between the feeding/fasting cycle and the properties of BA-regulated metabolic pathways. Whether BA alterations are associated per se with MAFLD remains inconclusive. However, increased fasting circulating BAs level was associated with higher risk of advanced fibrosis stage. Thus, for patients with MAFLD, dynamically monitoring the circulating BA profiles may be a promising tool for the stratification of MAFLD. CONCLUSIONS Alterations in the concentration, composition, and rhythm of circulating BAs are associated with adverse events in systemic metabolism. Subsequent investigations regarding these aspects of circulating BA kinetics may help predict future metabolic disorders and guide therapeutic interventions.
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Affiliation(s)
- Li Qi
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, 110022, Liaoning Province, China
| | - Yu Tian
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China
| | - Yongsheng Chen
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning Province, China
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Azer SA, Hasanato R. Use of bile acids as potential markers of liver dysfunction in humans: A systematic review. Medicine (Baltimore) 2021; 100:e27464. [PMID: 34731122 PMCID: PMC8519223 DOI: 10.1097/md.0000000000027464] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/05/2021] [Accepted: 09/20/2021] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE This study aimed to determine the effectiveness of using total, individual serum, or urinary bile acids (BA) as potential markers of liver dysfunction. METHODS We searched the PubMed and Web of Science databases using the following keywords- "serum bile acids," "liver dysfunction," "liver injury," "liver disease," "traditional liver function tests," "Chronic liver disease," "acute liver injury". The search was complemented by manual screening of the list of references for relevant articles. We selected only English-language manuscripts for adult patients based on predetermined inclusion and exclusion criteria. Animal studies and studies on neonates and children were not included. OUTCOME MEASURES Changes in BA concentrations or ratios at or prior to changes in liver function tests. RESULTS A total of 547 studies were identified, of which 28 were included after reading the entire manuscript. These studies included 1630 patients and 836 controls published between 1990 and 2017. The methods used in BA assays varied significantly, and the studies did not agree. on specific individual BA or BA ratios as biomarkers of specific liver injury or dysfunction. Except for the prognostic value of BA in intrahepatic cholestasis of pregnancy (ICP), studies have failed to provide evidence for BA as a liver biomarker. CONCLUSIONS Despite the research conducted on BA for over 27 years, there are inconsistencies in the reported results and a lack of solid evidence to support the use of individual BA or BA ratios as biomarkers of liver injury. Adequately conducted studies needed to resolve this limitation in the literature.
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Affiliation(s)
- Samy A. Azer
- Gastroenterologist and Chair of Curriculum Development and Research Unit, Department of Medical Education, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Rana Hasanato
- Clinical Biochemistry Consultant and Chair of Biochemistry Unit, Director of the Laboratories at King Saud University Medical City, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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Meessen ECE, Sips FLP, Eggink HM, Koehorst M, Romijn JA, Groen AK, van Riel NAW, Soeters MR. Model-based data analysis of individual human postprandial plasma bile acid responses indicates a major role for the gallbladder and intestine. Physiol Rep 2021; 8:e14358. [PMID: 32170845 PMCID: PMC7070101 DOI: 10.14814/phy2.14358] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Bile acids are multifaceted metabolic compounds that signal to cholesterol, glucose, and lipid homeostasis via receptors like the Farnesoid X Receptor (FXR) and transmembrane Takeda G protein-coupled receptor 5 (TGR5). The postprandial increase in plasma bile acid concentrations is therefore a potential metabolic signal. However, this postprandial response has a high interindividual variability. Such variability may affect bile acid receptor activation. METHODS In this study, we analyzed the inter- and intraindividual variability of fasting and postprandial bile acid concentrations during three identical meals on separate days in eight healthy lean male subjects using a statistical and mathematical approach. MAIN FINDINGS The postprandial bile acid responses exhibited large interindividual and intraindividual variability. The individual mathematical models, which represent the enterohepatic circulation of bile acids in each subject, suggest that interindividual variability results from quantitative and qualitative differences of distal active uptake, colon transit, and microbial bile acid transformation. Conversely, intraindividual variations in gallbladder kinetics can explain intraindividual differences in the postprandial responses. CONCLUSIONS We conclude that there is considerable inter- and intraindividual variation in postprandial plasma bile acid levels. The presented personalized approach is a promising tool to identify unique characteristics of underlying physiological processes and can be applied to investigate bile acid metabolism in pathophysiological conditions.
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Affiliation(s)
- Emma C E Meessen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - Fianne L P Sips
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Hannah M Eggink
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands
| | - Johannes A Romijn
- Department of Internal Medicine, Amsterdam University Medical Centers, Academic Medical Center (AMC), The Netherlands
| | - Albert K Groen
- Department of Laboratory Medicine, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.,Department of Vascular Medicine, Amsterdam University Medical Centers Amsterdam, Academic Medical Center (AMC), The Netherlands
| | - Natal A W van Riel
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.,Department of Vascular Medicine, Amsterdam University Medical Centers Amsterdam, Academic Medical Center (AMC), The Netherlands
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Academic Medical Center (AMC), Amsterdam, The Netherlands
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Distinct Postprandial Bile Acids Responses to a High-Calorie Diet in Men Volunteers Underscore Metabolically Healthy and Unhealthy Phenotypes. Nutrients 2020; 12:nu12113545. [PMID: 33228154 PMCID: PMC7699492 DOI: 10.3390/nu12113545] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/10/2020] [Accepted: 11/18/2020] [Indexed: 12/30/2022] Open
Abstract
Bile acids (BAs) regulate dietary lipid hydrolysis and absorption in the proximal intestine. Several studies have highlighted a determinant role of circulating levels and/or metabolism of BAs in the pathogenesis of major cardiometabolic diseases. Whether changes in BA profiles are causative or are consequence of these diseases remains to be determined. Healthy male volunteers (n = 71) underwent a postprandial exploration following consumption of a hypercaloric high fat typical Western meal providing 1200 kcal. We investigated variations of circulating levels of 28 BA species, together with BA synthesis marker 7α-hydroxy-4-cholesten-3-one (C4) over an approximately diurnal 12 h period. Analysis of BA variations during the postprandial time course revealed two major phenotypes with opposite fluctuations, i.e., circulating levels of each individual species of unconjugated BAs were reduced after meal consumption whereas those of tauro- and glyco-conjugated BAs were increased. By an unbiased classification strategy based on absolute postprandial changes in BA species levels, we classified subjects into three distinct clusters; the two extreme clusters being characterized by the smallest absolute changes in either unconjugated-BAs or conjugated-BAs. Finally, we demonstrated that our clustering based on postprandial changes in BA profiles was associated with specific clinical and biochemical features, including postprandial triglyceride levels, BMI or waist circumference. Altogether, our study reveals that postprandial profiles/patterns of BAs in response to a hypercaloric high fat challenge is associated with healthy or unhealthy metabolic phenotypes that may help in the early identification of subjects at risk of developing metabolic disorders.
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Devriendt N, Serrano G, Paepe D, de Rooster H. Liver function tests in dogs with congenital portosystemic shunts and their potential to determine persistent shunting after surgical attenuation. Vet J 2020; 261:105478. [PMID: 32741493 DOI: 10.1016/j.tvjl.2020.105478] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 05/24/2020] [Accepted: 05/29/2020] [Indexed: 02/03/2023]
Abstract
Portosystemic shunts (PSS) are congenital or acquired vascular anomalies that cause blood to bypass the liver. Liver function tests, such as fasting ammonia, ammonia tolerance test, and (paired) serum bile acids, are reliable for the diagnosis of PSS in dogs. Surgical attenuation is a common treatment for congenital PSS. Following surgical attenuation, it is useful to evaluate shunt closure. In this critical review, the ability of liver function tests to determine the presence and degree of residual shunting following surgical attenuation of canine PSS is discussed. Despite the availability of several liver function tests, a single rapid, simple, cost-effective, sensitive and specific test to evaluate surgical attenuation of PSS is not available.
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Affiliation(s)
- Nausikaa Devriendt
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
| | - Gonçalo Serrano
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Dominique Paepe
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Hilde de Rooster
- Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
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Hepatic Bile Acid Reuptake in the Rat Depends on Bile Acid Conjugation but Not on Agonistic Properties towards FXR and TGR5. Molecules 2020; 25:molecules25102371. [PMID: 32443832 PMCID: PMC7288213 DOI: 10.3390/molecules25102371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/25/2020] [Accepted: 05/13/2020] [Indexed: 11/24/2022] Open
Abstract
Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are the two known bile acid (BA) sensitive receptors and are expressed in the intestine and liver as well as in extra-enterohepatic tissues. The physiological effects of extra-enterohepatic FXR/TRG5 remain unclear. Further, the extent BAs escape liver reabsorption and how they interact with extra-enterohepatic FXR/TGR5 is understudied. We investigated if hepatic BA reuptake differed between BAs agonistic for FXR and TGR5 compared to non-agonists in the rat. Blood was collected from the portal vein and inferior caval vein from anesthetized rats before and 5, 20, 30, and 40 min post stimulation with sulfated cholecystokinin-8. Plasma concentrations of 20 different BAs were assessed by liquid chromatography coupled to mass spectrometry. Total portal vein BA AUC was 3–4 times greater than in the vena cava inferior (2.7 ± 0.6 vs. 0.7 ± 0.2 mM x min, p < 0.01, n = 8) with total unconjugated BAs being 2–3-fold higher than total conjugated BAs (AUC 8–10 higher p < 0.05 for both). However, in both cases, absolute ratios varied greatly among different BAs. The average hepatic reuptake of BAs agonistic for FXR/TGR5 was similar to non-agonists. However, as the sum of non-agonist BAs in vena portae was 2–3-fold higher than the sum agonist (p < 0.05), the peripheral BA pool was composed mostly of non-agonist BAs. We conclude that hepatic BA reuptake varies substantially by type and does not favor FXR/TGR5 BAs agonists.
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9
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Comprehensive evaluation of the metabolic effects of insect meal from Tenebrio molitor L. in growing pigs by transcriptomics, metabolomics and lipidomics. J Anim Sci Biotechnol 2020; 11:20. [PMID: 32158542 PMCID: PMC7055059 DOI: 10.1186/s40104-020-0425-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 01/06/2020] [Indexed: 12/13/2022] Open
Abstract
Background The hypothesis was tested that insect meal (IM) as protein source influences intermediary metabolism of growing pigs. To test this, 30 male, 5-week-old crossbred pigs were randomly assigned to 3 groups of 10 pigs each with similar body weights (BW) and fed isonitrogenous diets either without (CON) or with 5% IM (IM5) or 10% IM (IM10) from Tenebrio molitor L. for 4 weeks and key metabolic tissues (liver, muscle, plasma) were analyzed using omics-techniques. Results Most performance parameters did not differ across the groups, whereas ileal digestibilities of most amino acids were 6.7 to 15.6%-units lower in IM10 than in CON (P < 0.05). Transcriptomics of liver and skeletal muscle revealed a total of 166 and 198, respectively, transcripts differentially expressed between IM10 and CON (P < 0.05). Plasma metabolomics revealed higher concentrations of alanine, citrulline, glutamate, proline, serine, tyrosine and valine and a lower concentration of asparagine in IM10 than in CON (P < 0.05). Only one out of fourteen quantifiable amino acid metabolites, namely methionine sulfoxide (MetS), in plasma was elevated by 45% and 71% in IM5 and IM10, respectively, compared to CON (P < 0.05). Plasma concentrations of both, major carnitine/acylcarnitine species and bile acids were not different across groups. Lipidomics of liver and plasma demonstrated no differences in the concentrations of triacylglycerols, cholesterol and the main phospholipids, lysophospholipids and sphingolipids between groups. The percentages of all individual phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species in the liver showed no differences between groups, except those with 6 double bonds (PC 38:6, PC 40:6, PE 38:6, PE 40:6), which were markedly lower in IM10 than in CON (P < 0.05). In line with this, the percentage of C22:6n-3 in hepatic total lipids was lower in IM10 than in the other groups (P < 0.05). Conclusions Comprehensive analyzes of the transcriptome, lipidome and metabolome of key metabolic tissues indicate that partial or complete replacement of a conventional protein source by IM in the diet has only a weak impact on the intermediary metabolism of growing pigs. Thus, it is concluded that IM from Tenebrio molitor L. can be used as a dietary source of protein in pigs without causing adverse effects on metabolism.
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Ringseis R, Gessner DK, Eder K. The Gut-Liver Axis in the Control of Energy Metabolism and Food Intake in Animals. Annu Rev Anim Biosci 2019; 8:295-319. [PMID: 31689373 DOI: 10.1146/annurev-animal-021419-083852] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recent research has convincingly demonstrated a bidirectional communication axis between the gut and liver that enables the gut microbiota to strongly affect animals' feeding behavior and energy metabolism. As such, the gut-liver axis enables the host to control and shape the gut microbiota and to protect the intestinal barrier. Gut microbiota-host communication is based on several gut-derived compounds, such as short-chain fatty acids, bile acids, methylamines, amino acid-derived metabolites, and microbial-associated molecular patterns, which act as communication signals, and multiple host receptors, which sense the signals, thereby stimulating signaling and metabolic pathways in all key tissues of energy metabolism and food intake regulation. Disturbance in the microbial ecosystem balance, or microbial dysbiosis, causes profound derangements in the regulation of appetite and satiety in the hypothalamic centers of the brain and in key metabolic pathways in peripheral tissues owing to intestinal barrier disruption and subsequent induction of hepatic and hypothalamic inflammation.
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Affiliation(s)
- Robert Ringseis
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany;
| | - Denise K Gessner
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany;
| | - Klaus Eder
- Institute of Animal Nutrition and Nutrition Physiology, Justus-Liebig-University Giessen, 35392 Giessen, Germany;
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Baier V, Cordes H, Thiel C, Castell JV, Neumann UP, Blank LM, Kuepfer L. A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients. Front Physiol 2019; 10:1192. [PMID: 31611804 PMCID: PMC6777137 DOI: 10.3389/fphys.2019.01192] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 09/03/2019] [Indexed: 12/23/2022] Open
Abstract
Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.
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Affiliation(s)
- Vanessa Baier
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Henrik Cordes
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - Christoph Thiel
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - José V Castell
- Unit of Experimental Hepatology, IIS Hospital La Fe, Faculty of Medicine, University of Valencia and CIBEREHD, Valencia, Spain
| | - Ulf P Neumann
- Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Lars M Blank
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - Lars Kuepfer
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
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12
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van Nierop FS, Meessen ECE, Nelissen KGM, Achterbergh R, Lammers LA, Vaz FM, Mathôt RAA, Klümpen HJ, Olde Damink SW, Schaap FG, Romijn JA, Kemper EM, Soeters MR. Differential effects of a 40-hour fast and bile acid supplementation on human GLP-1 and FGF19 responses. Am J Physiol Endocrinol Metab 2019; 317:E494-E502. [PMID: 31237451 DOI: 10.1152/ajpendo.00534.2018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In experiment 1: we tested 4-h mixed meal after an overnight fast and a 40-h fast. In experiment 2, we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In experiment 1, 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at specific time points. In experiment 2, administration of gDCA increased GLP-1 levels and lowered late postprandial glucose without effect on FGF19. Energy expenditure was not affected by gDCA administration. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19, where the former appeared bile acid independent and the latter bile acid dependent. Second, a single dose of gDCA increased postprandial GLP-1. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by bile acids.
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Affiliation(s)
- F Samuel van Nierop
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, The Netherlands
| | - Emma C E Meessen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, The Netherlands
| | - Kyra G M Nelissen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, The Netherlands
| | - Roos Achterbergh
- Department of Internal Medicine, Amsterdam University Medical Centers, The Netherlands
| | - Laureen A Lammers
- Department of Hospital Pharmacy, Amsterdam University Medical Centers, The Netherlands
| | - Frédéric M Vaz
- Department of Clinical Chemistry, Amsterdam University Medical Centers, The Netherlands
| | - Ron A A Mathôt
- Department of Hospital Pharmacy, Amsterdam University Medical Centers, The Netherlands
| | - Heinz-Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, The Netherlands
| | - Steven W Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Frank G Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Johannes A Romijn
- Department of Internal Medicine, Amsterdam University Medical Centers, The Netherlands
| | - E Marleen Kemper
- Department of Hospital Pharmacy, Amsterdam University Medical Centers, The Netherlands
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, The Netherlands
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13
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van Nierop FS, de Jonge C, Kulik W, Bouvy N, Schaap FG, Olde Damink SW, Rensen S, Romijn JA, Greve JWM, Soeters MR. Duodenal-jejunal lining increases postprandial unconjugated bile acid responses and disrupts the bile acid-FXR-FGF19 axis in humans. Metabolism 2019; 93:25-32. [PMID: 30658059 DOI: 10.1016/j.metabol.2018.12.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 12/21/2018] [Accepted: 12/29/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile acid levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement. METHODS We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement. RESULTS Both fasting and postprandial bile acid levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile acid species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandial plasma courses were unaffected. CONCLUSIONS DJBL placement leads to profound increases in unconjugated bile acid levels after 6 months, similar to the effects of bariatric surgery. The temporal dissociation between the changes in bile acids, GLP-1 and FGF19 and other gut hormone responses warrant caution about the beneficial role of bile acids after DJBL placement. This observational uncontrolled study emphasizes the need for future controlled studies.
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Affiliation(s)
- Frederik Samuel van Nierop
- Amsterdam UMC, University of Amsterdam, Department of Endocrinology and Metabolism, Amsterdam Gastroenterology & Metabolism Research Institute, Meibergdreef 9, Amsterdam, the Netherlands
| | - Charlotte de Jonge
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands
| | - Wim Kulik
- Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam, the Netherlands
| | - Nicole Bouvy
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands
| | - Frank G Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands; Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Steven W Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands; Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany.; Department of Surgery, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Sander Rensen
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands
| | - Johannes A Romijn
- Amsterdam UMC, University of Amsterdam, Department of Medicine, Meibergdreef 9, Amsterdam, the Netherlands
| | - Jan Willem M Greve
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, the Netherlands; Department of General Surgery, Zuyderland Medical Center, Heerlen-Sittard, the Netherlands
| | - Maarten R Soeters
- Amsterdam UMC, University of Amsterdam, Department of Endocrinology and Metabolism, Amsterdam Gastroenterology & Metabolism Research Institute, Meibergdreef 9, Amsterdam, the Netherlands.
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14
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Eggink HM, van Nierop FS, Schooneman MG, Boelen A, Kalsbeek A, Koehorst M, ten Have GA, de Brauw LM, Groen AK, Romijn JA, Deutz NE, Soeters MR. Transhepatic bile acid kinetics in pigs and humans. Clin Nutr 2018; 37:1406-1414. [DOI: 10.1016/j.clnu.2017.06.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 06/13/2017] [Accepted: 06/13/2017] [Indexed: 01/06/2023]
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15
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Sips FLP, Eggink HM, Hilbers PAJ, Soeters MR, Groen AK, van Riel NAW. In Silico Analysis Identifies Intestinal Transit as a Key Determinant of Systemic Bile Acid Metabolism. Front Physiol 2018; 9:631. [PMID: 29951001 PMCID: PMC6008656 DOI: 10.3389/fphys.2018.00631] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/11/2018] [Indexed: 01/13/2023] Open
Abstract
Bile acids fulfill a variety of metabolic functions including regulation of glucose and lipid metabolism. Since changes of bile acid metabolism accompany obesity, Type 2 Diabetes Mellitus and bariatric surgery, there is great interest in their role in metabolic health. Here, we developed a mathematical model of systemic bile acid metabolism, and subsequently performed in silico analyses to gain quantitative insight into the factors determining plasma bile acid measurements. Intestinal transit was found to have a surprisingly central role in plasma bile acid appearance, as was evidenced by both the necessity of detailed intestinal transit functions for a physiological description of bile acid metabolism as well as the importance of the intestinal transit parameters in determining plasma measurements. The central role of intestinal transit is further highlighted by the dependency of the early phase of the dynamic response of plasma bile acids after a meal to intestinal propulsion.
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Affiliation(s)
- Fianne L P Sips
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands
| | - Hannah M Eggink
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Peter A J Hilbers
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Albert K Groen
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.,Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Natal A W van Riel
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.,Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
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16
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Mertens KL, Kalsbeek A, Soeters MR, Eggink HM. Bile Acid Signaling Pathways from the Enterohepatic Circulation to the Central Nervous System. Front Neurosci 2017; 11:617. [PMID: 29163019 PMCID: PMC5681992 DOI: 10.3389/fnins.2017.00617] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 10/23/2017] [Indexed: 12/14/2022] Open
Abstract
Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS). Bile acid signaling to the CNS encompasses both direct and indirect pathways. Bile acids can act directly in the brain via central FXR and TGR5 signaling. In addition, there are two indirect pathways that involve intermediate agents released upon interaction with bile acids receptors in the gut. Activation of intestinal FXR and TGR5 receptors can result in the release of fibroblast growth factor 19 (FGF19) and glucagon-like peptide 1 (GLP-1), both capable of signaling to the CNS. We conclude that when plasma bile acids levels are high all three pathways may contribute in signal transmission to the CNS. However, under normal physiological circumstances, the indirect pathway involving GLP-1 may evoke the most substantial effect in the brain.
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Affiliation(s)
- Kim L Mertens
- Master's Program in Biomedical Sciences, University of Amsterdam, Amsterdam, Netherlands
| | - Andries Kalsbeek
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Laboratory of Endocrinology, Department Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.,Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Hannah M Eggink
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
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17
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Eggink HM, Oosterman JE, de Goede P, de Vries EM, Foppen E, Koehorst M, Groen AK, Boelen A, Romijn JA, la Fleur SE, Soeters MR, Kalsbeek A. Complex interaction between circadian rhythm and diet on bile acid homeostasis in male rats. Chronobiol Int 2017; 34:1339-1353. [PMID: 29028359 DOI: 10.1080/07420528.2017.1363226] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Desynchronization between the master clock in the brain, which is entrained by (day) light, and peripheral organ clocks, which are mainly entrained by food intake, may have negative effects on energy metabolism. Bile acid metabolism follows a clear day/night rhythm. We investigated whether in rats on a normal chow diet the daily rhythm of plasma bile acids and hepatic expression of bile acid metabolic genes is controlled by the light/dark cycle or the feeding/fasting rhythm. In addition, we investigated the effects of high caloric diets and time-restricted feeding on daily rhythms of plasma bile acids and hepatic genes involved in bile acid synthesis. In experiment 1 male Wistar rats were fed according to three different feeding paradigms: food was available ad libitum for 24 h (ad lib) or time-restricted for 10 h during the dark period (dark fed) or 10 h during the light period (light fed). To allow further metabolic phenotyping, we manipulated dietary macronutrient intake by providing rats with a chow diet, a free choice high-fat-high-sugar diet or a free choice high-fat (HF) diet. In experiment 2 rats were fed a normal chow diet, but food was either available in a 6-meals-a-day (6M) scheme or ad lib. During both experiments, we measured plasma bile acid levels and hepatic mRNA expression of genes involved in bile acid metabolism at eight different time points during 24 h. Time-restricted feeding enhanced the daily rhythm in plasma bile acid concentrations. Plasma bile acid concentrations are highest during fasting and dropped during the period of food intake with all diets. An HF-containing diet changed bile acid pool composition, but not the daily rhythmicity of plasma bile acid levels. Daily rhythms of hepatic Cyp7a1 and Cyp8b1 mRNA expression followed the hepatic molecular clock, whereas for Shp expression food intake was leading. Combining an HF diet with feeding in the light/inactive period annulled CYp7a1 and Cyp8b1 gene expression rhythms, whilst keeping that of Shp intact. In conclusion, plasma bile acids and key genes in bile acid biosynthesis are entrained by food intake as well as the hepatic molecular clock. Eating during the inactivity period induced changes in the plasma bile acid pool composition similar to those induced by HF feeding.
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Affiliation(s)
- Hannah M Eggink
- a Department Endocrinology and Metabolism , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands
| | - Johanneke E Oosterman
- b Laboratory of Endocrinology, Deptartment Clinical Chemistry, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Paul de Goede
- b Laboratory of Endocrinology, Deptartment Clinical Chemistry, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Emmely M de Vries
- c Department of Medicine , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands
| | - Ewout Foppen
- b Laboratory of Endocrinology, Deptartment Clinical Chemistry, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Martijn Koehorst
- d Department of Laboratory Medicine , University of Groningen, University Medical Centre Groningen , Groningen , The Netherlands
| | - Albert K Groen
- d Department of Laboratory Medicine , University of Groningen, University Medical Centre Groningen , Groningen , The Netherlands.,e Department of Vascular Medicine, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Anita Boelen
- b Laboratory of Endocrinology, Deptartment Clinical Chemistry, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands
| | - Johannes A Romijn
- c Department of Medicine , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands
| | - Susanne E la Fleur
- a Department Endocrinology and Metabolism , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands.,b Laboratory of Endocrinology, Deptartment Clinical Chemistry, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands.,f Metabolism and Reward , Netherlands Institute for Neuroscience , Amsterdam , the Netherlands
| | - Maarten R Soeters
- a Department Endocrinology and Metabolism , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands
| | - Andries Kalsbeek
- a Department Endocrinology and Metabolism , Academic Medical Centre, University of Amsterdam , Amsterdam , The Netherlands.,b Laboratory of Endocrinology, Deptartment Clinical Chemistry, Academic Medical Centre , University of Amsterdam , Amsterdam , The Netherlands.,g Hypothalamic Integration Mechanisms , Netherlands Institute for Neuroscience , Amsterdam , The Netherlands
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18
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van Nierop FS, Scheltema MJ, Eggink HM, Pols TW, Sonne DP, Knop FK, Soeters MR. Clinical relevance of the bile acid receptor TGR5 in metabolism. Lancet Diabetes Endocrinol 2017; 5:224-233. [PMID: 27639537 DOI: 10.1016/s2213-8587(16)30155-3] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 06/23/2016] [Accepted: 06/23/2016] [Indexed: 01/01/2023]
Abstract
The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus on the translation of preclinical studies into clinically applicable findings. Studies in rodents suggest an important role for Tgr5 in Glp-1 secretion, insulin sensitivity, and energy expenditure. However, evidence of effects on these processes from human studies is less convincing. Ultimately, safe and selective human TGR5 agonists are needed to test the therapeutic potential of TGR5.
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Affiliation(s)
- F Samuel van Nierop
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Matthijs J Scheltema
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Hannah M Eggink
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands
| | - Thijs W Pols
- Department of Biochemistry, Academic Medical Center, Amsterdam, Netherlands
| | - David P Sonne
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Hellerup, Denmark
| | - Maarten R Soeters
- Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, Netherlands.
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19
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Haeusler RA, Camastra S, Nannipieri M, Astiarraga B, Castro-Perez J, Xie D, Wang L, Chakravarthy M, Ferrannini E. Increased Bile Acid Synthesis and Impaired Bile Acid Transport in Human Obesity. J Clin Endocrinol Metab 2016; 101:1935-44. [PMID: 26684275 PMCID: PMC4870845 DOI: 10.1210/jc.2015-2583] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT Alterations in bile acid (BA) synthesis and transport have the potential to affect multiple metabolic pathways in the pathophysiology of obesity. OBJECTIVE The objective of the study was to investigate the effects of obesity on serum fluctuations of BAs and markers of BA synthesis. DESIGN We measured BA fluctuations in 11 nonobese and 32 obese subjects and BA transporter expression in liver specimens from 42 individuals and specimens of duodenum, jejunum, ileum, colon, and pancreas from nine individuals. MAIN OUTCOME MEASURES We analyzed serum BAs and markers of BA synthesis after overnight fasting, during a hyperinsulinemic-euglycemic clamp, or a mixed-meal tolerance test and the association of BA transporter expression with body mass index. RESULTS BA synthesis markers were 2-fold higher (P < .01) and preferentially 12α-hydroxylated (P < .05) in obese subjects, and both measures were correlated with clamp-derived insulin sensitivity (r = -0.62, P < .0001, and r = -0.39, P = .01, respectively). Insulin infusion acutely reduced serum BAs in nonobese subjects, but this effect was blunted in obese subjects (δBAs -44.2% vs -4.2%, P < .05). The rise in serum BAs postprandially was also relatively blunted in obese subjects (δBAs +402% vs +133%, P < .01). Liver expression of the Na+-taurocholate cotransporting polypeptide and the bile salt export pump were negatively correlated with body mass index (r = -0.37, P = .02, and r = -0.48, P = .001, respectively). CONCLUSIONS Obesity is associated with increased BA synthesis, preferential 12α-hydroxylation, and impaired serum BA fluctuations. The findings reveal new pathophysiological aspects of BA action in obesity that may lend themselves to therapeutic targeting in metabolic disease.
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Affiliation(s)
- Rebecca A Haeusler
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Stefania Camastra
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Monica Nannipieri
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Brenno Astiarraga
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Jose Castro-Perez
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Dan Xie
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Liangsu Wang
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Manu Chakravarthy
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
| | - Ele Ferrannini
- Department of Pathology and Cell Biology (R.A.H.), Columbia University, New York, New York 10032; Department of Clinical and Experimental Medicine (S.C., M.N., B.A., E.F.), University of Pisa School of Medicine, 56100 Pisa, Italy; Merck Research Laboratories (J.C.-P., D.X., L.W., M.C.), Cardiometabolic Disease, Kenilworth, New Jersey 07033; and CNR Institute of Clinical Physiology (E.F.), 56100 Pisa, Italy
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Kim JU, Shariff MIF, Crossey MME, Gomez-Romero M, Holmes E, Cox IJ, Fye HKS, Njie R, Taylor-Robinson SD. Hepatocellular carcinoma: Review of disease and tumor biomarkers. World J Hepatol 2016; 8:471-484. [PMID: 27057305 PMCID: PMC4820639 DOI: 10.4254/wjh.v8.i10.471] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/02/2016] [Accepted: 03/16/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and now the second commonest global cause of cancer death. HCC tumorigenesis is relatively silent and patients experience late symptomatic presentation. As the option for curative treatments is limited to early stage cancers, diagnosis in non-symptomatic individuals is crucial. International guidelines advise regular surveillance of high-risk populations but the current tools lack sufficient sensitivity for early stage tumors on the background of a cirrhotic nodular liver. A number of novel biomarkers have now been suggested in the literature, which may reinforce the current surveillance methods. In addition, recent metabonomic and proteomic discoveries have established specific metabolite expressions in HCC, according to Warburg’s phenomenon of altered energy metabolism. With clinical validation, a simple and non-invasive test from the serum or urine may be performed to diagnose HCC, particularly benefiting low resource regions where the burden of HCC is highest.
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21
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Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review. Br J Cancer 2015; 112:1141-56. [PMID: 25826224 PMCID: PMC4385954 DOI: 10.1038/bjc.2015.38] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 11/04/2014] [Accepted: 12/20/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks third in overall global cancer-related mortality. Symptomatic presentation often means advanced disease where potentially curative treatment options become very limited. Numerous international guidelines propose the routine monitoring of those with the highest risk factors for the condition in order to diagnose potential tumourigenesis early. To aid this, the fields of metabonomic- and proteomic-based biomarker discovery have applied advanced tools to identify early changes in protein and metabolite expression in HCC patients vs controls. With robust validation, it is anticipated that from these candidates will rise a high-performance non-invasive test able to diagnose early HCC and related conditions. This review gathers the numerous markers proposed by studies using mass spectrometry and proton nuclear magnetic resonance spectroscopy and evaluates areas of consistency as well as discordance.
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Sonne DP, Lund A, Faber J, Holst JJ, Vilsbøll T, Knop FK. On the role of gallbladder emptying and incretin hormones for nutrient-mediated TSH suppression in patients with type 2 diabetes. Endocr Connect 2014; 3:193-9. [PMID: 25277744 PMCID: PMC4201783 DOI: 10.1530/ec-14-0088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T4) to the biologically active triiodothyronine (T3). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T3 and free T4) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T3 and T4 concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a 'gut-thyroid-pituitary' axis seems questionable.
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Affiliation(s)
- David P Sonne
- Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Asger Lund
- Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Jens Faber
- Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Jens J Holst
- Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Tina Vilsbøll
- Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark Department of MedicineCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, DenmarkDepartment of Biomedical SciencesFaculty of Health and Medical Sciences, The NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DenmarkDepartment of EndocrinologyHerlev Hospital, University of Copenhagen, Herlev, Denmark
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Hofmann AF, Hagey LR. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J Lipid Res 2014; 55:1553-95. [PMID: 24838141 DOI: 10.1194/jlr.r049437] [Citation(s) in RCA: 243] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Indexed: 12/12/2022] Open
Abstract
During the last 80 years there have been extraordinary advances in our knowledge of the chemistry and biology of bile acids. We present here a brief history of the major achievements as we perceive them. Bernal, a physicist, determined the X-ray structure of cholesterol crystals, and his data together with the vast chemical studies of Wieland and Windaus enabled the correct structure of the steroid nucleus to be deduced. Today, C24 and C27 bile acids together with C27 bile alcohols constitute most of the bile acid "family". Patterns of bile acid hydroxylation and conjugation are summarized. Bile acid measurement encompasses the techniques of GC, HPLC, and MS, as well as enzymatic, bioluminescent, and competitive binding methods. The enterohepatic circulation of bile acids results from vectorial transport of bile acids by the ileal enterocyte and hepatocyte; the key transporters have been cloned. Bile acids are amphipathic, self-associate in solution, and form mixed micelles with polar lipids, phosphatidylcholine in bile, and fatty acids in intestinal content during triglyceride digestion. The rise and decline of dissolution of cholesterol gallstones by the ingestion of 3,7-dihydroxy bile acids is chronicled. Scientists from throughout the world have contributed to these achievements.
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Affiliation(s)
- Alan F Hofmann
- Department of Medicine, University of California, San Diego, San Diego, CA
| | - Lee R Hagey
- Department of Medicine, University of California, San Diego, San Diego, CA
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Liaset B, Hao Q, Jørgensen H, Hallenborg P, Du ZY, Ma T, Marschall HU, Kruhøffer M, Li R, Li Q, Yde CC, Criales G, Bertram HC, Mellgren G, Øfjord ES, Lock EJ, Espe M, Frøyland L, Madsen L, Kristiansen K. Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. J Biol Chem 2011; 286:28382-95. [PMID: 21680746 PMCID: PMC3151081 DOI: 10.1074/jbc.m111.234732] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 06/01/2011] [Indexed: 12/31/2022] Open
Abstract
Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor β/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.
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Affiliation(s)
- Bjørn Liaset
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
| | - Qin Hao
- the Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Henry Jørgensen
- the Department of Animal Health, Welfare, and Nutrition, Aarhus University, 8830 Tjele, Denmark
| | - Philip Hallenborg
- the Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense Denmark
| | - Zhen-Yu Du
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
| | - Tao Ma
- the Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Hanns-Ulrich Marschall
- the Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
| | | | - Ruiqiang Li
- the Beijing Genomic Institute, Shenzhen 518083, China
| | - Qibin Li
- the Beijing Genomic Institute, Shenzhen 518083, China
| | - Christian Clement Yde
- the Department of Animal Health, Welfare, and Nutrition, Aarhus University, 8830 Tjele, Denmark
| | - Gabriel Criales
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
| | - Hanne C. Bertram
- the Department of Food Science, Aarhus University, 5792 Aarslev, Denmark
| | - Gunnar Mellgren
- the Institute of Medicine, University of Bergen, 5021 Bergen, Norway
- the Hormone Laboratory, Haukeland University Hospital, 5021 Bergen, Norway, and
| | | | - Erik-Jan Lock
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
| | - Marit Espe
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
| | - Livar Frøyland
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
| | - Lise Madsen
- From the National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway
- the Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Karsten Kristiansen
- the Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark
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Kawai H, Kudo N, Kawashima Y, Mitsumoto A. Efficacy of urine bile acid as a non-invasive indicator of liver damage in rats. J Toxicol Sci 2009; 34:27-38. [PMID: 19182433 DOI: 10.2131/jts.34.27] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Estimation of liver damage is important in the pathophysiological and toxicological study of liver disease. As a novel, non-invasive marker of liver damage, we studied the efficacy of urine bile acids (UBA) in a rat model of liver disease. Thioacetamide (TAA)-treated rats were used in this study. Single intraperitoneal administration of high-dose TAA induces severe damage to the liver, and thus is used as a model of acute hepatitis. Continuous administration of low-dose TAA yields mild damage to the liver, and induces cirrhosis and hepatic tumors. In this study, it was found that both acute and chronic administration of TAA was associated with a dose-dependent elevation of UBA. The elevation of UBA content correlated with the alteration of blood biochemical indicators, and UBA screening showed a remarkable ability to distinguish liver-damaged rats from healthy rats. In particular, UBA analysis was found to have high sensitivity, specificity, and positive predictive value for the screening of rats with abnormal serum alkaline phosphatase (ALP) activity due to chronic liver damage, which was confirmed to include cholestasis and subsequent cirrhosis by liver histological analysis. In conclusion, we demonstrated that measurement of UBA is a simple, non-invasive and effective method for the screening of cholestasis in TAA-treated rats. We suggest that UBA analysis may have potent applicability for monitoring the progress of liver damage in animal models of chronic liver disease, such as cirrhosis and hepatic encephalopathy.
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Affiliation(s)
- Hiroshi Kawai
- Faculty of Pharmaceutical Sciences, Josai International University, 1 Gumyo, Togane, Chiba 283-8555, Japan.
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Hofmann AF. Bile acids: trying to understand their chemistry and biology with the hope of helping patients. Hepatology 2009; 49:1403-18. [PMID: 19296471 DOI: 10.1002/hep.22789] [Citation(s) in RCA: 125] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
An informal review of the author's five decades of research on the chemistry and biology of bile acids in health and disease is presented. The review begins with a discussion of bile acid structure and its remarkable diversity in vertebrates. Methods for tagging bile acids with tritium for metabolic or transport studies are summarized. Bile acids solubilize polar lipids in mixed micelles; progress in elucidating the structure of the mixed micelle is discussed. Extensive studies on bile acid metabolism in humans have permitted the development of physiological pharmacokinetic models that can be used to simulate bile acid metabolism. Consequences of defective bile acid biosynthesis and transport have been clarified, and therapy has been developed. Methods for measuring bile acids have been improved. The rise and fall of medical and contact dissolution of cholesterol gallstones is chronicled. Finally, principles of therapy with bile acid agonists and antagonists are given. Advances in understanding bile acid biology and chemistry have helped to improve the lives of patients with hepatobiliary or digestive disease.
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Affiliation(s)
- Alan F Hofmann
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, San Diego, CA 92093-0063, USA.
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28
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Foley DP, Ricciardi R, Traylor AN, McLaughlin TJ, Donohue SE, Wheeler SM, Meyers WC, Quarfordt SH. Effect of hepatic artery flow on bile secretory function after cold ischemia. Am J Transplant 2003; 3:148-55. [PMID: 12603210 DOI: 10.1034/j.1600-6143.2003.00008.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
These studies evaluated the influence of hepatic arterial flow on biliary secretion after cold ischemia. Preparation of livers for transplantation or hepatic support impairs biliary secretion. The earliest indication of cold preservation injury during reperfusion is circulatory function. Arterial flow at this time may be critical for bile secretion. Porcine livers were isolated, maintained at 4 degrees for 2 h and connected in an extracorporeal circuit to an anesthetized normal pig. The extracorporeal livers were perfused either by both the hepatic artery and portal vein (dual) or by the portal vein alone (single). Incremental doses of sodium taurocholate were infused into the portal vein of both the dual and single perfused livers, and the bile secretion was compared. Most endogenous bile acids are lost during hepatic isolation. After supplementation, the biliary secretion of phosphatidyl choline and cholesterol was significantly better in the dual than single vessel-perfused livers; however, no difference was seen in bilirubin output. Single perfused livers were completely unable to increase biliary cholesterol in response to bile acid. The dependence of bile cholesterol secretion on arterial flow indicates the importance of this flow to the detoxification of compounds dependent on phosphatidyl choline transport during early transplantation.
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Affiliation(s)
- David P Foley
- Department of Surgery, University of Massachusetts Medical School, MA MCP Hahnemann University School of Medicine, Philadelphia, PA, USA
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29
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Lindor KD, Lacerda MA, Jorgensen RA, DeSotel CK, Batta AK, Salen G, Dickson ER, Rossi SS, Hofmann AF. Relationship between biliary and serum bile acids and response to ursodeoxycholic acid in patients with primary biliary cirrhosis. Am J Gastroenterol 1998; 93:1498-504. [PMID: 9732932 DOI: 10.1111/j.1572-0241.1998.00470.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Ursodeoxycholic acid (UDCA) improves liver biochemistries and enriches the bile with UDCA in patients with primary biliary cirrhosis. The aim of this study was to determine whether the degree of enrichment of bile correlated with that of serum and whether either of these measures correlated with improvement in measures of liver disease. METHODS In a randomized study, biliary and serum bile acid analyses were performed at entry and after 2 yr of UDCA or placebo. RESULTS The percentage of ursodeoxycholic acid in bile increased by 42% in the UDCA group (n = 61) compared with 8% in the placebo group (n = 57) (p < 0.0001). Measurement of serum bile acids in 32 patients (18 ursodeoxycholic acid, 14 placebo) indicated that at 2 yr, ursodeoxycholic acid comprised 65% of serum bile acids in the treated group and 7% in the placebo group. Agreement between bile and serum was fair (r = 0.75, p < or = 0.00002) because in some patients, plasma but not biliary bile acids were enriched with UDCA. Changes in biliary ursodeoxycholic acid correlated significantly but weakly with the changes in serum alkaline phosphatase, AST, bilirubin, and in Mayo risk score. Correlations between changes in serum bile acid composition and biochemical measures of disease activity were even weaker. CONCLUSION The measurement of biliary bile acids is superior to that of serum bile acids for assessing the compliance and changes in the circulating bile acids in patients receiving ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Furthermore, measures to further increase the proportion of ursodeoxycholic acid in circulating bile acids should be explored.
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Affiliation(s)
- K D Lindor
- Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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Abdelshaheed NN, Goldberg DM. Biochemical tests in diseases of the intestinal tract: their contributions to diagnosis, management, and understanding the pathophysiology of specific disease states. Crit Rev Clin Lab Sci 1997; 34:141-223. [PMID: 9143817 DOI: 10.3109/10408369709049587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Biochemical testing plays a major role in the complete evaluation of patients with suspected or established intestinal disease. We have classified these tests according to the medium in which they are performed: breath tests, including isotopic and nonisotopic tests, fecal tests, urine tests, serum tests, tissue tests, and other tests. The principles of various tests are outlined, and the role of each test in the evaluation of particular gastrointestinal disorders is discussed.
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Affiliation(s)
- N N Abdelshaheed
- Department of Clinical Biochemistry, Faculty of Medicine, University of Toronto, Banting Institute, Ontario, Canada
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31
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Garry FB, Fettman MJ, Curtis CR, Smith JA. Serum bile acid concentrations in dairy cattle with hepatic lipidosis. J Vet Intern Med 1994; 8:432-8. [PMID: 7884730 DOI: 10.1111/j.1939-1676.1994.tb03263.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
This study was designed to evaluate serum bile acid measurements as indicatory, of liver function and/or hepatic fat infiltration in dairy cattle. Serum bile acid concentrations were measured in healthy dairy cattle at different stages of lactation after fasting or feeding. Bile acid concentrations were compared with liver fat content and sulfobromophthalein (BSP) half-life (T 1/2). Serum bile acid concentrations were higher in cows in early lactation and with higher daily milk production. Compared with prefasting values, bile acid concentrations were decreased at 8, 14, and 24 hours of fasting. Blood samples from fed cows at 1- to 2-hour intervals had wide and inconsistent variations in bile acid concentration. Because serum bile acids correlated well with BSP T 1/2, it is suggested that both measurements evaluate a similar aspect of liver function. Neither bile acids nor BSP T 1/2 correlated with differences in liver fat content among cows. Because of large variability in serum bile acid concentrations in fed cows and the lack of correlation of measured values with liver fat content, bile acid determinations do not appear useful for showing changes in hepatic function in fed cows with subclinical hepatic lipidosis nor serve as a screening test for this condition.
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Affiliation(s)
- F B Garry
- Department of Clinical Sciences, Colorado State University, College of Veterinary Medicine and Biomedical Sciences, Fort Collins
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32
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Salemans JM, Nagengast FM, Tangerman A, Van Schaik A, de Haan AF, Jansen JB. Postprandial conjugated and unconjugated serum bile acid levels after proctocolectomy with ileal pouch-anal anastomosis. Scand J Gastroenterol 1993; 28:786-90. [PMID: 8235434 DOI: 10.3109/00365529309104010] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In patients with ileal pouch-anal anastomosis (IPAA) bile acid reabsorption may be impaired, and stasis may lead to deconjugation and dehydroxylation of bile acids as a result of bacterial overgrowth. We therefore studied fasting and postprandial conjugated and unconjugated serum levels of cholic (CA), chenodeoxycholic (CDCA), and deoxycholic acid (DCA) in 11 patients who underwent proctocolectomy with IPAA and in 11 healthy controls. Fasting levels of conjugated DCA but not CA and CDCA were significantly lower in IPAA patients. Postprandially, conjugated bile acid levels were significantly lower in IPAA patients. Postprandial unconjugated CA levels were significantly higher and CDCA levels tended to be higher in IPAA patients, whereas unconjugated DCA levels were lower in IPAA patients. These data suggest that reabsorption of conjugated bile acids is impaired after IPAA; deconjugation of bile acids may result from bacterial overgrowth secondary to stasis in the pouch; and dehydroxylation of bile acids is decreased after proctocolectomy with IPAA.
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Affiliation(s)
- J M Salemans
- Dept. of Medicine, University Hospital, Nijmegen, The Netherlands
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33
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Salemans JM, Nagengast FM, Tangerman A, van Schaik A, Hopman WP, de Haan AF, Jansen JB. Effect of ageing on postprandial conjugated and unconjugated serum bile acid levels in healthy subjects. Eur J Clin Invest 1993; 23:192-8. [PMID: 8477795 DOI: 10.1111/j.1365-2362.1993.tb00761.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Colorectal cancer is a disease of elderly subjects. A decreased ileal absorption of bile acids in elderly subjects may lead to an increased exposure of the colonic mucosa to secondary bile acids. This may contribute to an enhanced risk of colorectal cancer. In this study fasting and postprandial conjugated and unconjugated serum levels of cholic, chenodeoxycholic, and deoxycholic acid in 12 elderly and 12 younger subjects were investigated. Intestinal transit time, gallbladder emptying and jejunal bacterial flora were also studied in both age groups. Fasting levels of conjugated and unconjugated serum bile acids were similar in both age groups. Postprandial levels of all individual conjugated bile acids increased to a significantly higher extent in the younger subjects. Postprandial unconjugated serum bile acid levels did not differ significantly between both age groups, although unconjugated deoxycholic levels tended to increase to higher levels in the elderly. Results of jejunal bacterial counts, gallbladder emptying and intestinal transit time were similar in both groups. These data suggest that conjugated bile acids are reabsorbed less effectively in elderly subjects.
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Affiliation(s)
- J M Salemans
- Department of Medicine, University Hospital Nijmegen, The Netherlands
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34
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Rossi SS, Angellotti MA, Setchell KD, Hofmann AF. Measurement of total fasting-state serum bile acids: comparison of a solid-phase bioluminescence enzymatic assay, a homogeneous fluorescence enzymatic assay and isotope dilution gas chromatography-mass spectrometry. Clin Chim Acta 1991; 200:63-6. [PMID: 1934513 DOI: 10.1016/0009-8981(91)90337-c] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Cravetto C, Molino G, Hofmann AF, Belforte G, Bona B. Computer simulation of portal venous shunting and other isolated hepatobiliary defects of the enterohepatic circulation of bile acids using a physiological pharmacokinetic model. Hepatology 1988; 8:866-78. [PMID: 3391514 DOI: 10.1002/hep.1840080428] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The effect of three isolated defects in the enterohepatic circulation of bile acids on the size and distribution of the bile acid pool, plasma bile acid levels and bile acid secretion into the intestine was simulated using a linear multicompartmental physiological pharmacokinetic model previously used to simulate these aspects of bile acid metabolism in healthy man. Stepwise increases in portal-systemic shunting (with a reciprocal decrease in hepatic blood flow) caused an exponential increase in systemic plasma concentrations of bile acids, but no other major changes in bile acid metabolism. When the effect of varying fractional hepatic extraction was simulated, it was found that the greater the fractional hepatic extraction, the greater the elevation observed for systemic plasma bile acid levels for a given degree of portal-systemic shunting. When total hepatic blood flow was restored to normal by simulating "arterialization," systemic plasma levels of bile acids decreased strikingly, yet remained elevated. For cholate with a fractional hepatic extraction of 0.9 and 100% portal-systemic shunting, arterialization caused a decrease from a 20-fold elevation to a 5-fold elevation. This simulation thus defined the effect of the presence of the portal venous system per se on plasma bile acid levels and also quantified the circulatory route by which substances reach the liver when portal-systemic shunting is present. An isolated defect in hepatic uptake of bile acids caused little change in overall bile acid metabolism other than modestly increased plasma levels. Loss of bile acid storage by the gallbladder caused the majority of the bile acid pool to move from the gallbladder compartments to the proximal small intestine during fasting but had little effect on the dynamics of the enterohepatic circulation during eating. The results of these novel simulations of isolated defects in bile acid transport should aid in the interpretation of the more complex changes in bile acid metabolism which are likely to occur in hepatic or biliary disease.
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Affiliation(s)
- C Cravetto
- Ospedale S. Giovanni Battista e della Città di Torino, Dipartimento di Biomedicina, Università di Torino, Italy
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Penagini R, Spiller RC, Misiewicz JJ, Frost PG, Silk DB. Effect of cholecystectomy on mouth-to-cecum transit of a liquid meal. Dig Dis Sci 1988; 33:19-22. [PMID: 3338354 DOI: 10.1007/bf01536625] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Mouth-to-cecum transit and serum bile acid profile after ingestion of a lactulose-labeled liquid meal (440 kcal) were measured in eight patients with gallstones and a radiologically functioning gallbladder before and three to five months after cholecystectomy and in 15 controls. In the patients mouth-to-cecum transit was longer after the operation, 87.5 +/- 18.5 (mean +/- SEM) min vs 57.5 +/- 9.7 min (P less than 0.05). Mouth-to-cecum transit times before and after the operation were not different from controls (58.0 +/- 6.7 min). Serum bile acid AUCs were similar (P = NS) in patients and controls, while total bile acid and cholylglycine fasting concentrations were higher after cholecystectomy (P less than 0.05 and P less than 0.01 respectively). Cholecystectomy prolongs mouth-to-cecum transit of a liquid meal.
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Affiliation(s)
- R Penagini
- Department of Gastroenterology and Nutrition, Central Middlesex Hospital, London, England
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Mannes GA, Stellaard F, Paumgartner G. Diagnostic sensitivity of fasting and postprandial serum bile acids determined by different methods. Clin Chim Acta 1987; 162:147-54. [PMID: 3829420 DOI: 10.1016/0009-8981(87)90446-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The diagnostic sensitivities of serum bile acids determined by three different methods in the fasting and in the postprandial state were compared in 43 patients with cirrhosis of the liver. When a method with high analytical sensitivity (capillary gas-liquid chromatography, GLC, or radioimmunoassay, RIA) was used, the serum concentrations of bile acids exhibited similar diagnostic sensitivities in the fasting state (GLC, 98%; RIA, 93%) and in the postprandial state (GLC, 95%; RIA, 93%). By contrast, when an enzymatic method with limited analytical sensitivity was employed, the diagnostic sensitivity of fasting serum bile acids was lower (79%) than that of postprandial serum bile acids (93%). The measurement of individual serum bile acids by GLC did not add any further diagnostic information. The results of this study demonstrate that the diagnostic sensitivity of serum bile acids strongly depends on the analytical method used.
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Molino G, Hofmann AF, Cravetto C, Belforte G, Bona B. Simulation of the metabolism and enterohepatic circulation of endogenous chenodeoxycholic acid in man using a physiological pharmacokinetic model. Eur J Clin Invest 1986; 16:397-414. [PMID: 3100308 DOI: 10.1111/j.1365-2362.1986.tb01015.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The metabolism and enterohepatic circulation of chenodeoxycholic acid (CDC), a major primary bile acid in man, has been stimulated using a multicompartmental physiological pharmacokinetic model which was previously reported and used to simulate the metabolism of cholic acid. The model features compartments and linear transfer coefficients. Compartments, which are defined as the pools of single chemical species in well defined anatomical volumes, are aggregated into nine 'spaces' based on anatomical and physiological considerations (liver, gall-bladder, bile ducts, duodeno-jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). Each space contains several compartments which correspond to the compounds present in that space, for example, the compound in question and its biotransformation products. For CDC (as for cholic acid in the previous simulation) each space contains three compartments corresponding to the unconjugated bile acid, its glycine amidate, and its taurine amidate. Transfer coefficients, which denote the fractional amount of the compartment's contents exiting per unit time, are categorized according to function: flow, for example gall-bladder contraction (which involves transfer of all substances contained in the space at the same fractional rate); biotransformation (which transfers the substrate from one compartment to another within the same space); or transport (which denotes movements between contiguous compartments, belonging to different spaces across a diffusion membrane or a cellular barrier). The model is made time-dependent by incorporating meals which trigger gall-bladder emptying and modify intestinal flow. The transfer coefficients in the cholic acid model were modified for the CDC model since there is indirect evidence that CDC amidates (probably chenodeoxycholylglycine) are absorbed from the duodeno-jejunum and the first pass hepatic clearance of CDC species differs from that of cholyl species. The model was then used with all existing experimental data to simulate CDC metabolism in healthy humans over a 24-h period during which three meals were ingested. Satisfactory agreement was obtained between simulated and experimental data indicating that this model continues to be useful for describing the metabolism of bile acids and may also be of value for describing the metabolism of drugs whose metabolism is similar to that of bile acids.
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Schuster JJ, Stryker JA, Demers LM, Mortel R. Absence of bile acid malabsorption as a late effect of pelvic irradiation. Int J Radiat Oncol Biol Phys 1986; 12:1605-10. [PMID: 3759587 DOI: 10.1016/0360-3016(86)90285-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The pathophysiology of chronic radiation-induced diarrhea was evaluated in 28 patients who had undergone pelvic irradiation for gynecologic neoplasms 2 to 7 years previously. Twenty-seven patients undergoing radiotherapy with techniques that did not require abdominal or pelvic irradiation served as controls. The glycine conjugates of cholic acid (GC) were measured in serum by radioimmunoassay. Fasting and 2 hr. pp GC levels for the pelvic irradiated patients were 11.0 +/- 11.1 (mean +/- SD) and 24.8 +/- 17.3 micrograms/dl. Fasting and 2 hr. pp GC levels for controls were 12.6 +/- 7.4 and 28.0 +/- 14.7. There were no significant differences in the post-prandial increases in serum GC between pelvic irradiated patients and controls (p = .23, Type II error probability = .13). There was also no significant difference in the 2 hr. pp and fasting GC ratio (p = .39). There was significant difference between the stool frequency (p less than .01) and the prevalence of diarrhea (p less than .02) between pelvic irradiated patients and controls. The data suggest that bile acid malabsorption due to ileal dysfunction is not an inevitable late complication of pelvic irradiation and is not the major determinant in the pathophysiology of chronic radiation-induced diarrhea.
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Greenfield SM, Soloway RD, Carithers RL, Soper K, Silva de Barros SG, Balistreri WF. Evaluation of postprandial serum bile acid response as a test of hepatic function. Dig Dis Sci 1986; 31:785-91. [PMID: 3731971 DOI: 10.1007/bf01296044] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Commercial assays for serum bile acids (SBA) have made this measurement practical. The purpose of this study was to examine the utility of SBA measured every 30 min after a standardized meal in controls and in patients with acute viral hepatitis, cholestasis, and anicteric cirrhosis. In five controls, repeated examination of the area under the bile acid curve (AUC) was not statistically different, whereas the fasting and 2-hr postprandial levels were significantly different. In the group of patients with anicteric cirrhosis, AUC identified disease in 18/20 using total serum bile acids (TSBAs) and in 15/20 using cholylglycine (CG). AUC can be calculated from three samples obtained at 0, 60, and 120 min without losing the sensitivity achieved with seven serial samples. SGOT, alkaline phosphatase, and serum albumin were compared for sensitivity to the total SBA response curve in 20 patients with anicteric cirrhosis. SGOT and alkaline phosphatase identified only 50% and 55% as abnormal and serum albumin was less sensitive. Using total SBA, combining the fasting level and AUC identified 100% as abnormal; using CG, 85% of these patients were detected. As a stepwise cost-effective approach, the fasting level of SBAs can identify most patients with anicteric liver disease. In cases with normal fasting levels where liver disease is suspected, the three-point AUC determination may identify additional patients.
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Einarsson K, Ahlberg J, Angelin B, Björkhem I, Ewerth S. Portal venous bile acids in cholesterol gallstone disease: effect of treatment with chenodeoxycholic and cholic acids. Hepatology 1985; 5:661-5. [PMID: 4018738 DOI: 10.1002/hep.1840050423] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
We determined the serum concentrations of cholic, chenodeoxycholic and deoxycholic acids in portal and peripheral venous blood in 9 gallstone-free patients and 39 patients with cholesterol gallstones during standardized cholecystectomy. An accurate and specific gas chromatographic-mass spectrometric technique was used. The portal venous concentration of total bile acids was similar in gallstone-free and untreated gallstone patients (n = 20); there was no evidence of a reduced hepatic uptake of bile acids in the latter. Treatment with cholic acid (n = 10) was associated with a 70% increase in cholic acid and normal concentration of total bile acids. In chenodeoxycholic acid-treated patients (n = 9), the portal venous concentration of this bile acid was increased 3-fold; total bile acids were increased about 60%. The estimated hepatic uptake of cholic acid was slightly decreased during chenodeoxycholic acid treatment. The results indicate that neither bile acid inflow to the liver nor hepatic bile acid uptake is reduced in fasting patients with cholesterol gallstones, and treatment with chenodeoxycholic acid increases fasting inflow of bile acids to the liver. The latter may contribute to unsaturation of fasting hepatic bile during treatment with chenodeoxycholic acid.
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Bazzoli F, Fromm H, Roda A, Tunuguntla AK, Roda E, Barbara L, Amin P. Value of serum determinations for prediction of increased ursodeoxycholic and chenodeoxycholic levels in bile. Dig Dis Sci 1985; 30:650-4. [PMID: 4006647 DOI: 10.1007/bf01308414] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The correlation between biliary and serum levels of ursodeoxycholic and chenodeoxycholic acids was studied in a double-blind controlled manner in 39 patients before and during treatment with ursodeoxycholic acid, 800 mg/day; ursodeoxycholic acid, 400 mg/day; chenodeoxycholic acid, 750 mg/day; chenodeoxycholic acid, 375 mg/day; and placebo, respectively. On a total of 74 occasions, fasting duodenal bile and venous blood samples were obtained simultaneously. Biliary bile acid composition was determined by gas-liquid chromatography and serum ursodeoxycholic and chenodeoxycholic acid concentrations by radioimmunoassays. There was a much closer correlation between the biliary and serum levels of ursodeoxycholic acid (r = 0.8184, P less than 0.001) than between those of chenodeoxycholic acid (r = 0.4707, P less than 0.01). In contrast to serum chenodeoxycholic, which showed many overlaps between pre- and posttreatment values, serum ursodeoxycholic acid proved to be a very sensitive, specific, and convenient means of predicting the presence of increased levels of ursodeoxycholic acid in the enterohepatic cycle.
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Parraga ME, Kaneko JJ. Total serum bile acids and the bile acid profile as tests of liver function. Vet Res Commun 1985; 9:79-88. [PMID: 4002616 DOI: 10.1007/bf02215131] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Total serum bile acid assay for the evaluation of liver function has been available for many years but its application has been limited primarily by factors such as methodology, equipment and cost. New and improved methods for bile acid assay such as the radioimmunoassay or the hydroxysteroid dehydrogenase techniques have brought the assay for bile acids into the realm of the clinical laboratory. The efficacy of bile acids for clinical diagnostic use in the evaluation of liver function has not been firmly established. Newer methods using high pressure liquid chromatography to develop a profile of the different bile acids may clarify its usefulness and define its role among the many available tests of liver function in animals.
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van der Werf SD, van Berge Henegouwen GP, van den Broek W. Estimation of bile acid pool sizes from their spillover into systemic blood. J Lipid Res 1985. [DOI: 10.1016/s0022-2275(20)34386-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Hofmann AF, Roda A. Physicochemical properties of bile acids and their relationship to biological properties: an overview of the problem. J Lipid Res 1984. [DOI: 10.1016/s0022-2275(20)34421-7] [Citation(s) in RCA: 295] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Schoelmerich J, van Berge Henegouwen GP, Hofmann AF, DeLuca M. A bioluminescence assay for total 3 alpha-hydroxy bile acids in serum using immobilized enzymes. Clin Chim Acta 1984; 137:21-32. [PMID: 6583028 DOI: 10.1016/0009-8981(84)90308-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
A bioluminescence assay for bile acids was developed using a co-immobilized 3 alpha-hydroxysteroid dehydrogenase, diaphorase, and bacterial luciferase. The assay was specific for bile acids containing a free 3 alpha-hydroxyl group, as well as androsterone. Light output was linear over a bile acid concentration range of 1-20 000 pmol. Intra-assay precision was 6.2-8.2% and the recovery of added standards was 92-110%. Comparison of results using the bioluminescence assay with those using gas liquid chromatography revealed an excellent correlation (r = 0.99, n = 31). Since the bioluminescence assay is rapid, sensitive, specific, and uses inexpensive reagents, it appears to be an ideal method for the measurement of total bile acids in serum.
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Joelsson B, Hultberg B, Isaksson A, Alwmark A, Gullstrand P, Bengmark S. Total fasting serum bile acids and beta-hexosaminidase in alcoholic liver disease. Clin Chim Acta 1984; 136:203-9. [PMID: 6229367 DOI: 10.1016/0009-8981(84)90293-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Total serum bile acid levels and beta-hexosaminidase activity were studied in 22 normal subjects, 35 non-cirrhotic patients with acute alcohol intoxication, 45 patients with alcoholic liver cirrhosis and 11 patients with alcoholic liver cirrhosis and surgical portal-systemic shunts. Comparison was made with traditional liver function tests. beta-Hexosaminidase was most frequently elevated in acute alcohol intoxication (94%) while total serum bile acids were elevated in all patients with alcoholic liver cirrhosis. Total serum bile acid levels were found to discriminate most efficiently between acute alcohol intoxication and liver cirrhosis. The combined determination of serum beta-hexosaminidase and total serum bile acids is proposed for evaluating alcoholic liver disease.
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Abstract
The effects of liver disease on caffeine plasma clearance (Cl) and on exhalation of 14CO2 following i.v. injection of 2 mu Ci of [3-methyl-14C]caffeine together with 125 mg of the unlabeled compound were measured in 15 patients with cirrhosis, 11 subjects with miscellaneous liver disease, and 10 normal volunteers. Compared to mean values for Cl (2.02 +/- S.D. 0.68 ml per min per kg) and t1/2 (3.8 +/- 0.9 hr) in normal volunteers, cirrhotics were characterized by highly significant reductions in Cl (to 0.76 +/- 0.40) and prolongation in t1/2 (to 13.7 +/- 13.0), whereas the volume of distribution (VD) remained relatively unchanged (0.57 +/- 0.16 vs. 0.64 +/- 0.13 liter per kg in normals). Cumulative 14CO2 production and specific activity of 14CO2 in breath decreased in parallel (r = 0.83) with Cl. Patients with miscellaneous liver disease exhibited only small changes in Cl and t1/2; however, 14CO2 parameters in breath appeared more sensitive in indicating the slight functional derangement. In view of the correlation (Rs = 0.83) of cumulative 14CO2 excretion with the initial disappearance constant for bromosulfophthalein, the caffeine breath test may be considered as a quantitative measure of hepatic microsomal activity; based on a surprisingly close, hyperbolic relationship between Cl and fasting caffeine plasma concentrations, the latter might serve as a simple guide to severity of liver disease.
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Festi D, Morselli Labate AM, Roda A, Bazzoli F, Frabboni R, Rucci P, Taroni F, Aldini R, Roda E, Barbara L. Diagnostic effectiveness of serum bile acids in liver diseases as evaluated by multivariate statistical methods. Hepatology 1983; 3:707-13. [PMID: 6618438 DOI: 10.1002/hep.1840030514] [Citation(s) in RCA: 61] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The aims of this study were to determine the diagnostic effectiveness of fasting and postprandial serum bile acid determinations in liver diseases, and to compare results with those of conventional liver function tests. In 322 patients with biopsy-proved liver disease and 93 healthy subjects, fasting and postprandial (2 hr) serum levels of cholic, chenodeoxycholic, and lithocholic acid conjugates and conventional liver function tests were evaluated. Data were subjected to variance and discriminant and factor analyses. Fasting serum bile acids were higher in patients when compared to controls and were significantly higher in severe than in mild liver diseases. Determination of cholic plus lithocholic acid provided the highest discrimination capacity. The percent of correct allocation was 75.4% for conventional liver function tests, 70.1% for fasting serum bile acids and increased to 79.6% when liver function tests plus serum bile acids were considered. Postprandial percentages were always lower than fasting. Factor analysis identified two factors possibly related to cytolysis and protein synthesis. The serum bile acid concentrations highly correlated with both factors. We conclude that serum bile acid determinations increase the diagnostic and discriminant capacities of liver function tests and are more sensitive and discriminant when obtained in fasting than postprandially.
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