ABSTRACT
OBJECTIVE: To explore the clinical features, fetal outcomes and serum bile acids (BAs) metabolism in asymptomatic hypercholanemia of pregnancy (AHP), as well as the comparison with those in intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies. METHODS: A study containing 676 pregnant women was performed to investigate the clinical informations, routine biochemical features and obstetric outcomes of AHP by the comparison with ICP and normal pregnancies. Within the study subjects, 203 pregnant women received prospective determination for 55 serum individual BAs based on a validated UPLC-QTOF-MS/MS method. The differences in clinical features and serum BAs metabolism among the three groups were then investigated. RESULTS: The risk of adverse fetal outcomes in AHP (28.3%) was significantly higher than that in normal pregnancies (8.9%, p < 0.001), but lower than that in ICP group (52.1%, p < 0.001). Multivariate statistics analysis indicated a distinctive serum BAs metabolic profiling among the three groups (PLS-DA, R2Y = 0.580, Q2 = 0.537). Levels of serum BAs especially for deoxycholic acid species were found remarkably elevated in AHP as compared to those in ICP. CONCLUSIONS: AHP group had distinguished clinical features and serum BAs metabolism as compared to ICP group and normal pregnancies.
Subject(s)
Bile Acids and Salts/blood , Cholestasis, Intrahepatic/metabolism , Cholic Acids/blood , Lipid Metabolism , Pregnancy Complications/metabolism , Steroid Metabolism, Inborn Errors/metabolism , Adult , Asymptomatic Diseases/epidemiology , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/epidemiology , Cholestasis, Intrahepatic/pathology , Cholic Acids/metabolism , Female , Fetus , Humans , Metabolomics/standards , Multivariate Analysis , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/epidemiology , Pregnancy Complications/pathology , Steroid Metabolism, Inborn Errors/blood , Steroid Metabolism, Inborn Errors/epidemiology , Steroid Metabolism, Inborn Errors/pathology , Tandem Mass SpectrometryABSTRACT
Knowledge about in vivo effects of human circulating C-6 hydroxylated bile acids (BAs), also called muricholic acids, is sparse. It is unsettled if the gut microbiome might contribute to their biosynthesis. Here, we measured a range of serum BAs and related them to markers of human metabolic health and the gut microbiome. We examined 283 non-obese and obese Danish adults from the MetaHit study. Fasting concentrations of serum BAs were quantified using ultra-performance liquid chromatography-tandem mass-spectrometry. The gut microbiome was characterized with shotgun metagenomic sequencing and genome-scale metabolic modeling. We find that tauro- and glycohyocholic acid correlated inversely with body mass index (P = 4.1e-03, P = 1.9e-05, respectively), waist circumference (P = 0.017, P = 1.1e-04, respectively), body fat percentage (P = 2.5e-03, P = 2.3e-06, respectively), insulin resistance (P = 0.051, P = 4.6e-4, respectively), fasting concentrations of triglycerides (P = 0.06, P = 9.2e-4, respectively) and leptin (P = 0.067, P = 9.2e-4). Tauro- and glycohyocholic acids, and tauro-a-muricholic acid were directly linked with a distinct gut microbial community primarily composed of Clostridia species (P = 0.037, P = 0.013, P = 0.027, respectively). We conclude that serum conjugated C-6-hydroxylated BAs associate with measures of human metabolic health and gut communities of Clostridia species. The findings merit preclinical interventions and human feasibility studies to explore the therapeutic potential of these BAs in obesity and type 2 diabetes.
Subject(s)
Bile Acids and Salts/blood , Clostridium/metabolism , Gastrointestinal Microbiome , Adiposity , Body Mass Index , Cholic Acids/blood , Chromatography, High Pressure Liquid , Clostridium/genetics , Deoxycholic Acid/blood , Female , Gastrointestinal Microbiome/genetics , Humans , Logistic Models , Male , Metagenomics , Middle Aged , Obesity/blood , Obesity/microbiology , Tandem Mass Spectrometry , Taurocholic Acid/blood , Waist CircumferenceABSTRACT
Hyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.
Subject(s)
Biomarkers/blood , Cholic Acids/blood , Cholic Acids/urine , Metabolic Diseases/diagnosis , Adult , Cohort Studies , Cross-Sectional Studies , Diabetes Mellitus, Type 2/metabolism , Feces/chemistry , Female , Humans , Longitudinal Studies , Male , Middle Aged , Obesity/metabolism , Overweight/metabolism , Prediabetic State/diagnosis , Prospective StudiesABSTRACT
Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.
Subject(s)
Cholic Acids/therapeutic use , Diabetes Mellitus, Experimental/drug therapy , Glucose/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Blood Glucose/analysis , Cell Line , Cholic Acids/blood , Cholic Acids/chemistry , Cholic Acids/pharmacology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Isoxazoles/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, G-Protein-Coupled/deficiency , Receptors, G-Protein-Coupled/genetics , Signal Transduction/drug effects , SwineSubject(s)
Cholic Acids/blood , Gallbladder/abnormalities , Gallstones/genetics , Organic Anion Transporters, Sodium-Dependent/deficiency , Steroid Metabolism, Inborn Errors/genetics , Symporters/deficiency , Adolescent , Animals , Cholic Acids/metabolism , Disease Models, Animal , Female , Gallbladder/pathology , Gallstones/metabolism , Gallstones/pathology , Humans , Infant , Male , Mice , Mice, Knockout , Organic Anion Transporters, Sodium-Dependent/genetics , Polymorphism, Single Nucleotide , Retrospective Studies , Species Specificity , Steroid Metabolism, Inborn Errors/blood , Steroid Metabolism, Inborn Errors/metabolism , Steroid Metabolism, Inborn Errors/pathology , Symporters/geneticsABSTRACT
BACKGROUND: The relationship between breast arterial calcification (BAC) and angiographic coronary artery disease (CAD) is uncertain. Some studies have shown a positive association between BAC and angiographically proven CAD, while other studies have shown no association. OBJECTIVE: Examine the association between visually detected BAC on mammography and CAD found on invasive coronary angiography (ICA) in women and compare the frequency of risk factors for CAD between women with normal and abnormal ICA. DESIGN: Retrospective. SETTING: Single tertiary care center. PATIENTS AND METHODS: A review of the radiology databases was performed for female patients who underwent both ICA and mammography within six months of each other. Cases were excluded if there was a history of CAD, such as coronary artery bypass graft or prior percutaneous coronary intervention. MAIN OUTCOME MEASURES: BAC as a predictor of obstructive CAD on ICA. SAMPLE SIZE: 203 Saudi women RESULTS: The association between age at catheterization and ICA was statistically significant ( P=.01). There was no association between BAC and abnormal ICA ( P=.108). Women with abnormal ICA were older than women with a normal ICA ( P=.01). There was a higher frequency of CAD risk factors among the patients with abnormal ICA, except for smoking. In the multiple logistic regression model, ICA was associated with age, a family history of CAD, diabetes mellitus, hypertension and hypercholesterolemia. BAC-positive women were older than BAC-negative women ( P=.0001). BAC was associated with age, diabetes, hypertension, and chronic kidney disease in the multiple logistic regression model. CONCLUSIONS: BAC on mammography did not predict angiographically proven CAD. There was a strong association between BAC and age and many other conventional CAD risk factors. LIMITATIONS: Relatively small sample, single-center retrospective study. CONFLICT OF INTEREST: None.
Subject(s)
Breast/blood supply , Coronary Artery Disease/epidemiology , Coronary Stenosis/epidemiology , Vascular Calcification/epidemiology , Age Factors , Aged , Breast/diagnostic imaging , Cardiac Catheterization , Cholic Acids/blood , Coronary Angiography , Coronary Artery Disease/diagnosis , Coronary Stenosis/diagnosis , Diabetes Mellitus/epidemiology , Female , Humans , Hypertension/epidemiology , Logistic Models , Mammography , Middle Aged , Saudi Arabia/epidemiology , Steroid Metabolism, Inborn Errors/epidemiology , Vascular Calcification/diagnostic imagingABSTRACT
BACKGROUND: Recent studies have suggested that hyperglycaemia influences the bile acid profile and concentrations of secondary bile acids in the gut. INTRODUCTION: This study aimed to measure changes in the bile acid profile in the gut, tissues, and faeces in type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). METHODS: T1D and T2D were established in a mouse model. Twenty-one seven-weeks old balb/c mice were randomly divided into three equal groups, healthy, T1D and T2D. Blood, tissue, urine and faeces samples were collected for bile acid measurements. RESULTS: Compared with healthy mice, T1D and T2D mice showed lower levels of the primary bile acid, chenodeoxycholic acid, in the plasma, intestine, and brain, and higher levels of the secondary bile acid, lithocholic acid, in the plasma and pancreas. Levels of the bile acid ursodeoxycholic acid were undetected in healthy mice but were found to be elevated in T1D and T2D mice. CONCLUSION: Bile acid profiles in other organs were variably influenced by T1D and T2D development, which suggests similarity in effects of T1D and T2D on the bile acid profile, but these effects were not always consistent among all organs, possibly since feedback mechanisms controlling enterohepatic recirculation and bile acid profiles and biotransformation are different in T1D and T2D.
Subject(s)
Cholic Acids/analysis , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Animals , Bile Acids and Salts/analysis , Bile Acids and Salts/blood , Bile Acids and Salts/urine , Blood Glucose/analysis , Brain Chemistry , Cholic Acids/blood , Cholic Acids/urine , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/urine , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/urine , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/urine , Disease Models, Animal , Feces/chemistry , Gastrointestinal Tract/chemistry , Hyperglycemia/blood , Hyperglycemia/urine , Male , Mice , Mice, Inbred BALB C , Muscles/chemistry , Random AllocationABSTRACT
OBJECTIVE: Bile acids (BAs) are important molecules in the progression of nonalcoholic fatty liver disease. This study aimed to investigate BA profile alterations in Chinese nonalcoholic steatohepatitis (NASH) patients. METHODS: BA profiles in serum and liver tissues were determined by ultraperformance liquid chromatography coupled to tandem mass spectrometry in patients from two different clinical centers. RESULTS: A total of 134 participants were enrolled in this study to serve as the training (n = 87) and validation (n = 47) cohorts. The ratio of circulating conjugated chenodeoxycholic acids to muricholic acids (P = 0.001) was elevated from healthy controls to non-NASH individuals to NASH individuals in a stepwise manner in the training cohort and was positively associated with the histological severity of NASH: steatosis (R2 = 0.12), lobular inflammation (R2 = 0.12), ballooning (R2 = 0.11), and fibrosis stage (R2 = 0.18). The ratio was elevated in the validation cohort of NASH patients (P < 0.001), and it was able to predict NASH (area under the receiver operating characteristic curve: 75%) and significant fibrosis (area under the receiver operating characteristic curve: 71%) in these two cohorts. Moreover, this elevated ratio and impaired farnesoid X receptor signaling were found in the NASH liver. CONCLUSIONS: Altered BA profile in NASH is closely associated with the severity of liver lesions, and it has the potential for predicting NASH development.
Subject(s)
Bile Acids and Salts/blood , Chenodeoxycholic Acid/blood , Cholic Acids/blood , Liver/pathology , Non-alcoholic Fatty Liver Disease/blood , Adult , Cohort Studies , Disease Progression , Female , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/pathology , Risk FactorsABSTRACT
BACKGROUND & AIMS: Fontan surgery for single ventricle congenital heart disease leads to Fontan-associated liver disease (FALD). Typical laboratory tests, imaging, and histopathology cannot predict clinical severity in FALD. HepQuant SHUNT is a proprietary serum test of hepatic function and physiology that has not yet been evaluated in FALD. METHODS: Fourteen adult FALD patients at a single urban tertiary care center who underwent a Fontan procedure in childhood received HepQuant SHUNT testing between September 2015 and April 2018. The HepQuant SHUNT disease severity index (DSI) assesses global liver function and physiology from systemic and portal hepatic filtration rates (HFRs, clearances adjusted for body mass) of orally and intravenously administered cholates labeled with deuterium or 13C. The SHUNT parameter of the test measures portal systemic shunting from the ratio of Systemic HFR to Portal HFR. Chart review included laboratory tests, imaging, and clinical findings. Data from FALD patients were compared with data from healthy controls. RESULTS: The average DSI and SHUNT values for the FALD patients were 17.5% and 36.1%, respectively, compared to 9.2% and 24.1%, respectively, for controls. Twelve (85.7%) FALD patients had a DSI >15 (upper limit of normal). Seven (50.0%) FALD patients had SHUNT values >30% (upper limit of normal), while three FALD patients (21.4%) had SHUNT values >49%. One FALD patient with preoperative SHUNT of 69%, who underwent a combined heart-liver transplant, had confirmed cirrhotic morphology within the liver explant. CONCLUSIONS: This pilot study demonstrated that most FALD patients had hepatic impairment detected by abnormal DSI, with a smaller number having markedly elevated SHUNT values >49% suggesting intrinsic liver disease. The HepQuant SHUNT test may be useful in detecting and quantifying liver disease severity in FALD patients.
Subject(s)
Cholic Acids/administration & dosage , Fontan Procedure/adverse effects , Heart Defects, Congenital/surgery , Liver Circulation , Liver Diseases/diagnosis , Liver Function Tests , Administration, Intravenous , Adult , Case-Control Studies , Cholic Acids/blood , Cross-Sectional Studies , Female , Heart Defects, Congenital/diagnostic imaging , Heart Defects, Congenital/physiopathology , Hepatobiliary Elimination , Humans , Liver Diseases/etiology , Liver Diseases/physiopathology , Male , Middle Aged , Pilot Projects , Predictive Value of Tests , Proof of Concept Study , Severity of Illness Index , Young AdultABSTRACT
Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia.
Subject(s)
Cholic Acids/blood , Gastrointestinal Microbiome , Intestinal Reabsorption , Pregnancy/blood , Receptors, Cytoplasmic and Nuclear/metabolism , Amidohydrolases/genetics , Animals , Bacteroides/isolation & purification , Cecum/drug effects , Cecum/microbiology , Cholic Acids/pharmacology , Enterocytes/drug effects , Female , Humans , Mice, Inbred C57BL , Receptors, Cytoplasmic and Nuclear/agonistsABSTRACT
Cholestane-3ß,5α,6ß-triol (3ß,5α,6ß-triol) is formed from cholestan-5,6-epoxide (5,6-EC) in a reaction catalysed by cholesterol epoxide hydrolase, following formation of 5,6-EC through free radical oxidation of cholesterol. 7-Oxocholesterol (7-OC) and 7ß-hydroxycholesterol (7ß-HC) can also be formed by free radical oxidation of cholesterol. Here we investigate how 3ß,5α,6ß-triol, 7-OC and 7ß-HC are metabolised to bile acids. We show, by monitoring oxysterol metabolites in plasma samples rich in 3ß,5α,6ß-triol, 7-OC and 7ß-HC, that these three oxysterols fall into novel branches of the acidic pathway of bile acid biosynthesis becoming (25R)26-hydroxylated then carboxylated, 24-hydroxylated and side-chain shortened to give the final products 3ß,5α,6ß-trihydroxycholanoic, 3ß-hydroxy-7-oxochol-5-enoic and 3ß,7ß-dihydroxychol-5-enoic acids, respectively. The intermediates in these pathways may be causative of some phenotypical features of, and/or have diagnostic value for, the lysosomal storage diseases, Niemann Pick types C and B and lysosomal acid lipase deficiency. Free radical derived oxysterols are metabolised in human to unusual bile acids via novel branches of the acidic pathway, intermediates in these pathways are observed in plasma.
Subject(s)
Cholestanols/blood , Cholic Acids/blood , Hydroxycholesterols/blood , Ketocholesterols/blood , Lysosomal Storage Diseases/blood , Niemann-Pick Diseases/blood , Wolman Disease/blood , Biotransformation , Cholesterol/blood , Cholic Acids/biosynthesis , Chromatography, Liquid , Epoxide Hydrolases/blood , Free Radicals/blood , Humans , Hydroxylation , Lysosomal Storage Diseases/physiopathology , Mass Spectrometry , Niemann-Pick Diseases/physiopathology , Oxidation-Reduction , Wolman Disease/physiopathology , Wolman DiseaseABSTRACT
BACKGROUND: Familial hypercholesterolemia could be prevalent among patients with acute coronary syndrome. OBJECTIVE: To investigate both the frequency of causative mutations for familial hypercholesterolemia (FH) and the optimal selection of patients for genetic testing among patients with an acute coronary syndrome (ACS). METHODS: One hundred and sixteen patients with an ACS during 2009-2015 were identified through the SWEDEHEART registry. Patients who had either a high total cholesterol level ≥7 mmol L-1 combined with a triglyceride level ≤2.6 mmol L-1 , or were treated with lipid-lowering medication and had a total cholesterol level >4.9 mmol L-1 and a triglyceride level ≤2.6 mmol L-1 were included. Genetic testing was performed first with a regionally designed FH mutation panel (118 mutations), followed by testing with a commercially available FH genetic analysis (Progenika Biopharma). RESULTS: A total of 6.9% (8/116) patients had a FH-causative mutation, all in the LDL-receptor. Five patients were detected on the panel, and further testing of the remaining 111 patients detected an additional 3 FH-causative mutations. Baseline characteristics were similar in FH-positive and FH-negative patients with respect to age, gender, prior ACS and diabetes. Patients with a FH-causative mutation had higher Dutch Lipid Clinical Network (DLCN) score (5.5 (5.0-6.5) vs 3.0 (2.0-5.0), P < 0.001) and a higher low-density lipoprotein level (5.7 (4.7-6.5) vs 4.9 (3.5-5.4), P = 0.030). The Dutch Lipid Clinical Network (DLCN) score had a good discrimination with an area under the curve of 0.856 (95% CI 0.763-0.949). CONCLUSION: Genetic testing for FH should be considered in patients with ACS and high DLCN score.
Subject(s)
Acute Coronary Syndrome/genetics , Cholic Acids/blood , Genetic Testing , Steroid Metabolism, Inborn Errors/genetics , Acute Coronary Syndrome/etiology , Aged , Cholesterol/blood , Cholic Acids/genetics , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Middle Aged , Steroid Metabolism, Inborn Errors/complications , Survivors , Triglycerides/bloodABSTRACT
Familial hypercholesterolemia (FH) conveys a high risk of premature atherosclerosis as a result of lifelong exposure to high LDL cholesterol levels that are not fully reduced by standard-of-care lipid-lowering treatment. Inflammatory mediators have played a role in the progression of atherosclerotic lesions. Here, we investigated whether innate immunity cells in patients with FH have a specific proinflammatory phenotype that is distinct from that of cells in normal participants. To this end, miR-505-3p-a microRNA related to chronic inflammation-and its target genes were investigated in monocyte-derived macrophages (MACs) of patients with FH (FH-MACs) and non-FH controls (co-MACs). On the basis of the profiler PCR array analysis of agomiR-505-3p-transfected MACs, we identified the chemokine receptors, CCR3, CCR4, and CXCR1, as genes that are regulated by miR-505-3p via the transcription factor, RUNX1. miR-505-3p was significantly down-regulated, whereas CCR3, CCR4, CXCR, and RUNX1 were increased in FH-MAC compared with co-MAC, with the increase being more evident in the proinflammatory M1-like FH-MAC. Chemokine receptor levels were unrelated to LDL plasma levels at entry, but correlated with age in patients with FH, not in controls. In summary, we demonstrate for first time to our knowledge that MACs from FH-MACs have an inflammatory phenotype that is characterized by the up-regulation of CCR3, CCR4, and CXCR1 under the control of miR-505-3p. These results suggest a chronic inflammatory condition in FH innate immunity cells that is not reverted by standard lipid-lowering treatment.-Escate, R., Mata, P., Cepeda, J. M., Padró, T., Badimon, L. miR-505-3p controls chemokine receptor up-regulation in macrophages: role in familial hypercholesterolemia.
Subject(s)
Cholic Acids/blood , Macrophages/metabolism , MicroRNAs/metabolism , Receptors, Chemokine/biosynthesis , Steroid Metabolism, Inborn Errors/metabolism , Up-Regulation , Cholic Acids/immunology , Cholic Acids/metabolism , Female , Humans , Macrophages/immunology , Macrophages/pathology , Male , MicroRNAs/immunology , Receptors, Chemokine/immunology , Steroid Metabolism, Inborn Errors/immunology , Steroid Metabolism, Inborn Errors/pathology , Steroid Metabolism, Inborn Errors/therapyABSTRACT
BACKGROUND: Bile acids (BAs) are post-prandial hormones that play an important role in glucose and lipid homeostasis as well as energy expenditure. Total and glycine-amidated BAs increase after sleeve gastrectomy (SG) and correlate to improved metabolic disease. No specific bile acid subtype has been shown conclusively to mediate the weight loss effect. Therefore, the objective of this study was to prospectively evaluate the comprehensive changes in meal-stimulated BAs after SG and determine if a specific change in the BA profile correlates to the early weight loss response. METHODS: Patients were prospectively enrolled at the University of Nebraska Medical Center who were undergoing a SG for treatment of morbid obesity. Primary and secondary plasma bile acids and their amidated (glycine, G-, or taurine, T-) subtypes were measured at fasting, 30 and 60 min after a liquid meal performed pre-op, and at 6 and 12 weeks post-op. Area under the curve (AUC) was calculated for the hour meal test for each bile acid subtype. BAs that were significantly increased post-op were correlated to body mass index (BMI) loss. RESULTS: Total BA AUC was significantly increased at 6 (p < 0.01) and 12 weeks post-op (p < 0.01) compared to pre-operative values. The increase in total BA AUC was due to a statistically significant increase in G-BAs. Nine different BA AUC subtypes were significantly increased at both 6 and 12 weeks post-op. Increased total and G-chenodeoxycholic acid AUC was significantly correlated to the 6 week BMI loss (p = 0.03). Increased G-hyocholic acid was significantly correlated to increased weight loss at both 6 (p = 0.05) and 12 weeks (p = 0.006). CONCLUSIONS: SG induced an early and persistent post-prandial surge in multiple bile acid subtypes. Increased G-hyocholic consistently correlated with greater early BMI loss. This study provides evidence for a role of BAs in the surgical weight loss response after SG.
Subject(s)
Cholic Acids/blood , Gastrectomy , Weight Loss , Bile Acids and Salts/blood , Body Mass Index , Fasting , Female , Humans , Male , Middle Aged , Postprandial Period , Prospective StudiesABSTRACT
A simple, sensitive and rapid method using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was developed and validated for quantification of glycine-ß-muricholic acid (Gly-MCA) in mouse plasma for the first time. Plasma samples were pretreated with protein precipitation. The analyte and internal standard were separated on a Shimadzu Shim-pack XR-ODS column (4.6×50mm, 2.2µm) using 0.1% formic acid-water-methanol as mobile phase, with a runtime of 5min. Detection was performed using negative ion electrospray tandem mass spectrometry via multiple reaction monitoring (MRM) scan mode. The linear range was 5ng-2µg/ml (correlation coefficient >0.995) for Gly-MCA with a lower limit of quantitation of 5ng/ml. The intra-day and inter-day precision were less than 9.2% for the analyte and accuracy was from 0.4% to 7.0%. This analytical method was then successfully applied to a pharmacokinetic study of Gly-MCA following oral administration and intraperitoneal injection in mice.
Subject(s)
Cholic Acids/blood , Cholic Acids/chemistry , Glycine/blood , Glycine/chemistry , Plasma/chemistry , Animals , Chromatography, High Pressure Liquid/methods , Formates/chemistry , Male , Methanol/chemistry , Mice , Mice, Inbred C57BL , Reproducibility of Results , Tandem Mass Spectrometry/methods , Water/chemistryABSTRACT
Cardiovascular risk evaluation is a fundamental approach in cardiovascular prevention. Cardiovascular risk categories are associated with lipid-lowering drug intensity. LDL cholesterol is the main target of treatment. Statins are the first line lipid-lowering drugs. Lipid-lowering combination therapy is to be used in order to obtain the LDL cholesterol targets. Screening of familial hypercholesterolemia might be included in all prevention population strategy.
Subject(s)
Cardiovascular Diseases/prevention & control , Dyslipidemias/therapy , Anticholesteremic Agents/therapeutic use , Cholesterol, LDL/blood , Cholic Acids/blood , Diet, Mediterranean , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Liver Function Tests , Myalgia/chemically induced , Practice Guidelines as Topic , Risk Assessment , Steroid Metabolism, Inborn Errors/diagnosisABSTRACT
BACKGROUND: This study aimed to explore the related metabolic biomarkers and to observe the effects of Yangxin Decoction (YXD) on plasma metabolism of patients with unstable angina (UA). METHODS: In total, 10 patients with UA (intervention group) and 10 healthy participants (control group) were recruited for this study from January 2009 to December 2010. Plasma samples from both groups were analyzed using liquid chromatography mass spectrometry (LC-MS). Principle component analysis (PCA) and partial least squares (PLS) were used to explore the correlations between metabolic markers in patients with UA. RESULTS: The LC-MS results indicated that the serum levels of 5 potential metabolic markers, namely, ceramide, glycocholic acid, allocholic acid, lithocholic acid, and leukotriene (LT) B4, were significantly higher in the intervention group than those in the control group. CONCLUSION: The results of this study demonstrated potential metabolic markers that can be used to distinguish and diagnose patients with UA.
Subject(s)
Angina, Unstable/blood , Angina, Unstable/drug therapy , Drugs, Chinese Herbal/therapeutic use , Administration, Oral , Biomarkers/blood , Blood Chemical Analysis , Ceramides/blood , Cholic Acids/blood , Chromatography, Liquid , Female , Glycocholic Acid/blood , Humans , Leukotriene B4/blood , Lithocholic Acid/blood , Male , Mass Spectrometry , Metabolomics , Middle Aged , Principal Component AnalysisABSTRACT
BACKGROUND & AIMS: Hepatobiliary secretion of bile acids is an important liver function. Here, we quantified the hepatic transport kinetics of conjugated bile acids using the bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) and positron emission tomography (PET). METHODS: Nine healthy participants and eight patients with varying degrees of cholestasis were examined with 11C-CSar PET and measurement of arterial and hepatic venous blood concentrations of 11C-CSar. RESULTS: Results are presented as median (range). The hepatic intrinsic clearance was 1.50 (1.20-1.76) ml blood/min/ml liver tissue in healthy participants and 0.46 (0.13-0.91) in patients. In healthy participants, the rate constant for secretion of 11C-CSar from hepatocytes to bile was 0.36 (0.30-0.62)min-1, 20 times higher than the rate constant for backflux from hepatocytes to blood (0.02, 0.005-0.07min-1). In the patients, rate constant for transport from hepatocyte to bile was reduced to 0.12 (0.006-0.27)min-1, 2.3times higher than the rate constant for backflux to blood (0.05, 0.04-0.09). The increased backflux did not fully normalize exposure of the hepatocyte to bile acids as mean hepatocyte residence time of 11C-CSar was 2.5 (1.6-3.1)min in healthy participants and 6.4 (3.1-23.7)min in patients. The rate constant for transport of 11C-CSar from intrahepatic to extrahepatic bile was 0.057 (0.023-0.11)min-1 in healthy participants and only slightly reduced in patients 0.039 (0.017-0.066). CONCLUSIONS: This first in vivo quantification of individual steps involved in the hepatobiliary secretion of a conjugated bile acid in humans provided new insight into cholestatic disease. LAY SUMMARY: Positron emission tomography (PET) using the radiolabelled bile acid (11C-CSar) enabled quantification of the individual steps of the hepatic transport of bile acids from blood to bile in man. Cholestasis reduced uptake and secretion and increased backflux to blood. These findings improve our understanding of cholestatic liver diseases and may support therapeutic decisions. CLINICAL TRIAL REGISTRATION NUMBER: The trial is registered at ClinicalTrials.gov (NCT01879735).
Subject(s)
Bile Acids and Salts/metabolism , Cholestasis/metabolism , Cholic Acids/pharmacokinetics , Sarcosine/analogs & derivatives , Aged , Bile/metabolism , Biological Transport, Active , Carbon Radioisotopes , Case-Control Studies , Cholestasis/blood , Cholestasis/diagnostic imaging , Cholic Acids/blood , Female , Humans , Kinetics , Liver/diagnostic imaging , Liver/metabolism , Liver Circulation , Male , Middle Aged , Positron-Emission Tomography , Sarcosine/blood , Sarcosine/pharmacokinetics , Young AdultABSTRACT
A novel MRI blood-pool contrast agent (Gd-AAZTA-MADEC) has been compared with established blood pool agents for tumor contrast enhanced images and angiography. Synthesis, relaxometric properties, albumin binding affinity and pharmacokinetic profiles are reported. For in vivo studies, angiographic images and tumor contrast enhanced images were acquired on mice with benchtop 1T-MRI scanners and compared with MS-325, B22956/1 and B25716/1. The design of this contrast agent involved the elongation of the spacer between the targeting deoxycholic acid moiety and the Gd-AAZTA imaging reporting unit that drastically changed either the binding affinity to albumin (KA(HSA) = 8.3 × 10(5) M(-1)) and the hydration state of the Gd ion (q = 2) in comparison to the recently reported B25716/1. The very markedly high binding affinity towards mouse and human serum albumins resulted in peculiar pharmacokinetics and relaxometric properties. The NMRD profiles clearly indicated that maximum efficiency is attainable at magnetic field strength of 1 T. In vivo studies showed high enhancement of the vasculature and a prolonged accumulation inside tumor. The herein reported pre-clinical imaging studies show that a great benefit arises from the combination of a benchtop MRI scanner operating at 1 T and the albumin-binding Gd-AAZTA-MADEC complex, for pursuing enhanced angiography and improved characterization of tumor vascular microenvironment.