ABSTRACT
A growing body of evidence has linked the gut microbiota to liver metabolism. The manipulation of intestinal microflora has been considered as a promising avenue to promote liver health. However, the effects of Lactobacillus gasseri LA39, a potential probiotic, on liver metabolism remain unclear. Accumulating studies have investigated the proteomic profile for mining the host biological events affected by microbes, and used the germ-free (GF) mouse model to evaluate host-microbe interaction. Here, we explored the effects of L. gasseri LA39 gavage on the protein expression profiles of the liver of GF mice. Our results showed that a total of 128 proteins were upregulated, whereas a total of 123 proteins were downregulated by treatment with L. gasseri LA39. Further bioinformatics analyses suggested that the primary bile acid (BA) biosynthesis pathway in the liver was activated by L. gasseri LA39. Three differentially expressed proteins (cytochrome P450 family 27 subfamily A member 1 (CYP27A1), cytochrome P450 family 7 subfamily B member 1 (CYP7B1), and cytochrome P450 family 8 subfamily B member 1 (CYP8B1)) involved in the primary BA biosynthesis pathway were further validated by western blot assay. In addition, targeted metabolomic analyses demonstrated that serum and fecal β-muricholic acid (a primary BA), dehydrolithocholic acid (a secondary BA), and glycolithocholic acid-3-sulfate (a secondary BA) were significantly increased by L. gasseri LA39. Thus, our data revealed that L. gasseri LA39 activates the hepatic primary BA biosynthesis and promotes the intestinal secondary BA biotransformation. Based on these findings, we suggest that L. gasseri LA39 confers an important function in the gut‒liver axis through regulating BA metabolism.
Subject(s)
Mice , Animals , Bile Acids and Salts/metabolism , Lactobacillus gasseri , Proteomics , Liver/metabolism , BiotransformationABSTRACT
Over the past decade, there has been increasing attention on the interaction between microbiota and bile acid metabolism. Bile acids are not only involved in the metabolism of nutrients, but are also important in signal transduction for the regulation of host physiological activities. Microbial-regulated bile acid metabolism has been proven to affect many diseases, but there have not been many studies of disease regulation by microbial receptor signaling pathways. This review considers findings of recent research on the core roles of farnesoid X receptor (FXR), G protein-coupled bile acid receptor (TGR5), and vitamin D receptor (VDR) signaling pathways in microbial-host interactions in health and disease. Studying the relationship between these pathways can help us understand the pathogenesis of human diseases, and lead to new solutions for their treatments.
Subject(s)
Humans , Bile Acids and Salts/metabolism , Gastrointestinal Microbiome , Inflammation/metabolism , Metabolic Syndrome/metabolism , Receptors, Calcitriol/physiology , Receptors, Cytoplasmic and Nuclear/physiology , Receptors, G-Protein-Coupled/physiology , Signal Transduction/physiologyABSTRACT
Resumen: Introducción: Los errores innatos en la síntesis de ácidos biliares son un grupo de defectos genéticos que representan del 1 al 2% de las enfermedades colestásicas crónicas en lactantes, niños y adolescentes. La deficiencia de 3β-Δ5-C27-hidroxiesteroide oxidoreductasa (3β-HSDH) es el defecto más comúnmente reportado. El cuadro clínico característico consiste en hepatitis neonatal, hepatomegalia, esplenomegalia, malabsorción, desnutrición y enfermedad hepática de aparición tardía. Caso clínico: Lactante masculino con antecedente de ictericia en escleras a los 4 meses que se resolvió espontáneamente; posteriormente, a los 18 meses, presentó enfermedad colestásica. Durante su abordaje se documentó gamma-glutamil transpeptidasa normal, hallazgo que es altamente sugestivo de alteración en la síntesis de ácidos biliares. El diagnóstico se realizó con espectrometría de masas en orina. Se inició tratamiento con ácido cólico oral, y presentó mejoría inmediata. Conclusiones: El resultado en los ácidos biliares urinarios es definitivo para el defecto genético y consistente con mutaciones homocigotas en el gen HSD3B7. Este padecimiento constituye un diagnóstico de exclusión en las enfermedades colestásicas de la infancia, particularmente el hallazgo de gamma-glutamil transpeptidasa normal o levemente aumentada, y responde adecuadamente al tratamiento oral, por lo que debe identificarse de forma temprana.
Abstract: Background: Inborn errors in bile acid synthesis are a group of genetic defects accounting for 1 to 2% of chronic cholestatic diseases in infants, children and adolescents. Deficiency of 3β-Δ5-C27-hydroxysteroid dehydrogenase (3β-HSDH) is the most common defect in this disease. Clinical features consist of neonatal hepatitis, hepatomegaly, splenomegaly, malabsorption, malnutrition, and late-onset liver disease. Case report: A male infant who presented jaundice in sclera at 4 months that resolved spontaneously, later presented cholestatic disease at 18 months. During his approach, normal gamma-glutamyl transpeptidase was documented, a finding that is highly suggestive of alteration in the synthesis of bile acids. The diagnosis was made using urine mass spectrometry. Oral colic acid treatment was started, presenting immediate improvement. Conclusions: The result in urinary bile acids is definitive for the genetic defect and consistent with homozygous mutations in the HSD3B7 gene. This condition is a diagnosis of exclusion in childhood cholestatic diseases, particularly in the presence of normal or mildly enlarged gamma-glutamyl transpeptidase, and responds adequately to oral treatment; it should be identified early.
Subject(s)
Humans , Infant , Male , Bile Acids and Salts/metabolism , Cholestasis/diagnosis , 3-Hydroxysteroid Dehydrogenases/genetics , Metabolism, Inborn Errors/diagnosis , Cholestasis/genetics , Cholic Acid/administration & dosage , Jaundice/etiology , Metabolism, Inborn Errors/geneticsABSTRACT
El objetivo de esta revisión fue exponer el conocimiento actual sobre la relación existente entre dietas altas en grasa (DAG), alteraciones morfológicas de la mucosa intestinal, efectos inflamatorios y cáncer intestinal. Las DAG inicialmente producen aumento de la microbiota patógena, lo que reduce la cantidad y calidad de la secreción de los exocrinocitos caliciformes, disminuyendo la efectividad de la barrera intestinal. Las bacterias y sus lipopolisacaridos (LPS) promueven la secreción de citoquinas proinflamatorias activando vías de inflamación, que a su vez afectan la integridad de las uniones intercelulares alterando la barrera intestinal. Lo anterior, permite que los LPS ingresen a la lámina propia y circulación sanguínea produciendo inflamación local y sistémica. Así mismo, las DAG generan efectos nocivos en la morfología y función de la mucosa gastrointestinal lo que podría favorecer el desarrollo de cáncer. Lo anterior, podría deberse a que el consumo de DAG es capaz de aumentar la proliferación de células de la mucosa y el número y proliferación de células madres tumorales en el intestino.
The aim of this review was to present current knowledge about the relationship between high fat diets (HFD), morphological alterations of intestinal mucosa, inflammatory effects and intestinal cancer. The HFD initially produces an increase in the pathogenic microbiota, which reduces quantity and quality of secretion of goblet cells, decreasing the effectiveness of intestinal barrier. Bacteria and their lipopolysaccharides (LPS) stimulate the secretion of proinflammatory cytokines by activating inflammation pathways, which in turn affect the integrity of intercellular junctions by changing intestinal barrier. The above allows the LPS enter to lamina propria and blood circulation producing local and systemic inflammation. Likewise, HFD generate deleterious effects on morphology and function of gastrointestinal mucosa, which could favor the development of cancer. This could be due to the fact that consumption of HFD is capable of increasing proliferation of mucosal cells and number and proliferation of tumor stem cells in the intestine.
Subject(s)
Humans , Dietary Fats/adverse effects , Diet, High-Fat/adverse effects , Gastrointestinal Microbiome/drug effects , Inflammation/etiology , Intestinal Mucosa/drug effects , Bile Acids and Salts/metabolism , Cytokines/metabolism , Tight Junctions/drug effects , Gastrointestinal Tract/microbiology , Inflammation/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiologyABSTRACT
La colangitis biliar primaria (CBP), es una colangiopatía crónica caracterizada por la destrucción selectiva de las células epiteliales biliares de conductos hepáticos de pequeño y mediano calibre, que afecta principalmente a mujeres. Los principales síntomas son la fatiga y el prurito, sin embargo, gran porcentaje de los pacientes pueden ser asintomáticos. El diagnóstico se basa en anticuerpos antimitocondriales (AMA) con títulos >1:40, fosfatasa alcalina >1,5 veces del límite superior normal por más de 24 semanas e histología hepática compatible con la patología. Se asocia con múltiples enfermedades principalmente de carácter autoinmune extra hepáticas, enfermedades tiroideas, óseas, entre otras. El tratamiento de primera línea es el ácido ursodesoxicólico (AUDC) que a pesar que no cura la enfermedad, mejora las pruebas del perfil hepático, así como el retraso en la progresión a cirrosis. Actualmente se encuentran en estudio nuevos tratamientos y terapias adyuvantes. El propósito de esta revisión es ofrecer una actualización de este tema que se presenta en los servicios de medicina interna y gastroenterología; para su realización se conformó un equipo interdisciplinario que desarrolló una búsqueda en la base Medline a través de PubMed con las palabras claves correspondientes y se procedió a una lectura crítica y analítica de títulos, resúmenes y textos completos para el filtro, extracción y síntesis de la información encontrada
Primary biliary cholangitis (PBC) is a chronic autoimmune cholangiopathy characterized by a selective destruction of biliary epithelial cells of small and medium caliber hepatic ducts, which mainly affects women. The main symptoms are fatigue and pruritus, however, a large proportion of patients may be asymptomatic. The diagnosis is based on AMA titers >1:40, alkaline phosphatase >1.5 times the upper limit for more than 24 weeks and compatible liver histology. It is associated with multiple autoimmune diseases mainly extrahepatic, thyroid diseases, bone diseases, among others. The first line treatment is ursodeoxycholic acid (UDCA), that improves liver function tests and delay the progression to cirrhosis. Currently, there are new treatments and adjuvant therapies on study. The purpose of this review is to offer an update in this topic, which is very important in gastroenterology and internal medicine. We formed an interdisciplinary team to search in the database Medline thorough PubMed with the key words describe below, we made a critical lecture of the titles and abstracts of each article to write this paper
Subject(s)
Humans , Cholangitis , Pruritus/etiology , Autoantibodies/immunology , Autoimmune Diseases/physiopathology , Autoimmune Diseases/epidemiology , Urinary Tract Infections/complications , Ursodeoxycholic Acid/therapeutic use , Bile Acids and Salts/metabolism , Smoking/adverse effects , Cholangitis/complications , Cholangitis/physiopathology , Cholangitis/immunology , Cholangitis/epidemiology , Genetic Predisposition to Disease , Fatigue/etiology , Microbiota , Liver Cirrhosis, Biliary/etiology , Liver Cirrhosis, Biliary/prevention & control , Mitochondria/immunology , Antibody SpecificityABSTRACT
The main purpose of this study was to investigate bifidobacteria flora in fecal samples from children with rotavirus infection and determine the significance of their selected probiotic properties for improvement of health status. Enzyme-linked immunosorbent assay was used to identify rotavirus antigen in fecal samples from 94 patients with gastroenteritis and from 30 without gastroenteritis. Bifidobacteria were identified by selective media, gram reaction, colony morphology, fructose-6-phosphate phosphoketolase enzyme activity and classical identification tests. Exopolysaccharide (EPS) production was identified by phenol-sulphuric acid method. The modified method was then used to identify the quantity of taurocholic and glycocholic acid deconjugation and cholesterol elimination of the strains. Thirty-five of the 94 fecal samples were found positive for rotavirus antigen (37.23%). Bifidobacteria were identified in 59 of the samples. The EPS production ranges were 29.56-102.21 mg/L. The cholesterol elimination rates ranged between 8.36-39.22%. Furthermore, a positive and strong correlation was determined between EPS production and the presence of cholesterol (r=0.984, P<0.001). The deconjugation rates for the sodium glycocholate group was higher than the sodium taurocholate group. Rotavirus (+) bifidobacteria strains had higher EPS production, deconjugation rate and cholesterol elimination compared to bifidobacteria strains isolated from children in the rotavirus (-) sample and without gastroenteritis. Significant differences were observed among groups in all parameters (P<0.05). Given the increased number of rotavirus cases in Turkey and worldwide, it is very important to add superior bifidobacteria in the diets of infected children to improve the intestinal and vital functions.
Subject(s)
Humans , Child, Preschool , Polysaccharides, Bacterial/biosynthesis , Bifidobacterium/isolation & purification , Bile Acids and Salts/metabolism , Cholesterol/metabolism , Gastroenteritis/virology , Antigens, Viral/analysis , Rotavirus Infections/microbiology , Enzyme-Linked Immunosorbent Assay , Feces/virologyABSTRACT
OBJETIVO: Avaliar a prevalência da baixa densidade mineral óssea (DMO) em mulheres na pós-menopausa tratadas de câncer de mama. MÉTODOS: Estudo de corte transversal que incluiu 115 mulheres tratadas de câncer de mama atendidas em Hospital Universitário do Sudeste do Brasil. Foram incluídas mulheres com amenorreia há 12 meses ou mais e 45 anos ou mais de idade, tratadas de câncer de mama e livres de doença há pelo menos 5 anos. A DMO foi mensurada pelos raios-X de dupla energia em coluna lombar (L1 a L4) e colo de fêmur. Considerou-se baixa DMO quando valores de T-score de coluna total e/ou colo de fêmur <-1,0 Score de Delphi (DP) (osteopenia e osteoporose). Por meio de entrevista, foram avaliados fatores de risco para baixa DMO. Na análise estatística, empregaram-se os testes do χ2 ou Exato de Fisher. RESULTADOS: A média de idade das pacientes foi 61,6±10,1 anos e o tempo de menopausa, 14,2±5,6 anos, com tempo médio de seguimento de 10,1±3,9 anos. Considerando coluna e colo de fêmur, 60% das mulheres tratadas de câncer de mama apresentavam baixa DMO. Avaliando os fatores de risco para baixa DMO, foi encontrada diferença significativa na distribuição percentual quanto à idade (maior porcentagem de mulheres com mais de 50 anos e baixa DMO), história pessoal de fratura prévia (11,6% com baixa DMO e nenhuma com DMO normal) e índice de massa corpórea. Maior frequência de obesidade foi observada entre mulheres com DMO normal (63%) quando comparadas àquelas com baixa DMO (26,1%; p<0,05). CONCLUSÃO: Mulheres na pós-menopausa tratadas de câncer de mama apresentaram elevada prevalência de baixa DMO (osteopenia e/ou osteoporose). .
PURPOSE: To evaluate the prevalence of low bone mineral density (BMD) in postmenopausal breast cancer survivors. METHODS: In this cross-sectional study, 115 breast cancer survivors, seeking healthcare at a University Hospital in Brazil, were evaluated. Eligibility criteria included women with amenorrhea ≥12 months and age ≥45 years, treated for breast cancer and metastasis-free for at least five years. BMD was measured by DEXA at the lumbar spine (L1-L4) and femoral neck. Low BMD was considered when total-spine and/or femoral-neck T-score values were <-1.0 Delphi Score (DP) (osteopenia and osteoporosis). The risk factors for low BMD were assessed by interview. Data were analyzed statistically by the χ2 test and Fisher's exact test. RESULTS: The mean age of breast cancer survivors was 61.6±10.1 years and time since menopause was 14.2±5.6 years, with a mean follow-up of 10.1±3.9 years. Considering spine and femoral neck, 60% of breast cancer survivors had low BMD. By evaluating the risk factors for low BMD, a significant difference was found in the percent distribution for age (higher % of women >50 years with low BMD), personal history of previous fracture (11.6% with low BMD versus 0% with normal BMD) and BMI. A higher frequency of obesity was observed among women with normal BMD (63%) compared to those with low BMD (26.1%) (p<0.05). CONCLUSION: Postmenopausal breast cancer survivors had a high prevalence of osteopenia and osteoporosis. .
Subject(s)
Animals , Rats , Bile Acids and Salts/metabolism , Bile Canaliculi/metabolism , Carrier Proteins/metabolism , Hydroxysteroid Dehydrogenases , Membrane Glycoproteins , Adenosine Triphosphatases/metabolism , Biological Transport , COS Cells , Carcinoembryonic Antigen/biosynthesis , Carrier Proteins/biosynthesis , DNA Primers , DNA, Complementary , Ileum/metabolism , Kinetics , Mutagenesis, Site-Directed , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/metabolism , Transfection , Taurocholic Acid/metabolismABSTRACT
No abstract available.
Subject(s)
Female , Humans , Middle Aged , Bile Acids and Salts/metabolism , Bile Ducts, Intrahepatic/diagnostic imaging , Cholangiography , Gastroscopy , Magnetic Resonance Imaging , Stomach Diseases/diagnosisABSTRACT
Clonorchis sinensis is a biological carcinogen inducing human cholangiocarcinoma, and clonorchiasis is one of the important endemic infectious diseases in East Asia. The present study investigated survival longevity of C. sinensis adult worms in various in vitro conditions to find the best way of keeping the worms longer. The worms were maintained in 0.85% NaCl, 1xPBS, 1xLocke's solution, RPMI-1640, DMEM, and IMDM media, and in 1xLocke's solution with different supplements. All of the worms died within 3 and 7 days in 0.85% NaCl and 1xPBS, respectively, but survived up to 57 days in 1xLocke's solution. The worms lived for 106 days in DMEM, and 114 days in both RPMI-1640 and IMDM media. The survival rate in RPMI-1640 medium was the highest (50%) compared to that in DMEM (20+/-10%) and in IMDM (33.3+/-25.2%) after 3 months. The 1xLocke's solution with 0.005% bovine bile supplement showed increased duration of maximum survival from 42 days to 70 days. Higher concentration of bile supplements than 0.005% or addition of glucose were disadvantageous for the worm survival. The worms died rapidly in solutions containing L-aspartic acid, L-glutamic acid, and adenine compared to L-arginine, L-serine, and L-tryptophan. In conclusion, the 1xLocke's solution best supports the worms alive among inorganic solutions for 57 days, and the RPMI-1640 medium maintains living C. sinensis adults better and longer up to 114 days in vitro than other media.
Subject(s)
Animals , Cattle , Humans , Rabbits , Rats , Adenine/metabolism , Amino Acids/metabolism , Bile/parasitology , Bile Acids and Salts/metabolism , Cell Survival , Clonorchiasis/parasitology , Clonorchis sinensis/growth & development , Culture Media , Cyprinidae , Fish Diseases/parasitology , Time FactorsABSTRACT
Non-alcoholic fatty liver (NAFLD) is a clinical entity whose importance has been increasing, because of its potential progression to chronic liver disease. The alteration of bile secretory function may be a relevant factor of hepatic injury in NAFLD. Objectives: To assess basal bile secretory function and protein mass of three major hepatobiliary transporters in an experimental NAFLD model. Materials and Methods: The bile secretory function was determined by conventional techniques in Sprague-Dawley control rats fed with a choline-deficient diet (CDD) for 8 weeks. Protein mass of Ntcp, Bsep and Mrp2 was measured by western blot. Results: An impaired bile secretory function was observed in rats fed with DDC (reduction of bile flow and secretion of bile acids and organic anions). In addition, DDC fed rats showed higher levels of serum aminotransferases. Ntcp protein mass decreased in rats with DDC, while Bsep and Mrp2 did not show quantitative variations in this experimental model. Conclusions: In this experimental model of NAFLD an impaired bile secretory function was observed, determining a cholestatic pattern. The decrease in Ntcp protein mass with unaltered Bsep and Mrp2 protein mass, associated with a significant decrease in bile secretion suggests a functional impairment of these transporters in rats fed with DDC diet.
El hígado graso no alcohólico (HGNA) es una entidad clínica de importancia creciente por su potencial progresión a daño hepático crónico. La alteración de la función secretora biliar puede ser un factor relevante en el daño o lesión hepática asociada al HGNA. Objetivos: Evaluar la función secretora biliar basal y los niveles de expresión proteica de tres de los principales transportadores hepatobiliares en un modelo de HGNA experimental. Materiales y Métodos: La función secretora biliar fue determinada por técnicas convencionales en ratas Sprague-Dawley control y alimentadas con una dieta deficiente en colina (DDC) durante 8 semanas. Los niveles de expresión proteica de Ntcp, Bsep y Mrp2 fueron cuantificados por western blot. Resultados: Se observó un deterioro de la función secretora biliar en las ratas alimentadas con DDC (reducción del flujo biliar y de secreción de ácidos biliares y aniones orgánicos). Además, las ratas con DDC presentaron niveles más altos de transaminasas séricas. Los niveles de expresión proteica de Ntcp disminuyeron en las ratas con DDC, mientras que Bsep y Mrp2 no presentaron variaciones cuantitativas en este modelo experimental. Conclusiones: En este modelo de HGNA experimental se observó una función secretora biliar alterada, determinando un patrón colestásico. La disminución de los niveles de expresión proteica de Ntcp junto con la mantención de Bsep y Mrp2, asociados a una disminución significativa de la secreción biliar, sugiere un deterioro funcional de estos transportadores en ratas alimentadas con dieta DDC.
Subject(s)
Animals , Rats , Bile , Fatty Liver/physiopathology , Fatty Liver/metabolism , Cholestasis/metabolism , Choline Deficiency , Liver/pathology , Multidrug Resistance-Associated Proteins/metabolism , Rats, Sprague-Dawley , Organ Size , Organic Anion Transporters, Sodium-Dependent/metabolism , Blotting, Western , Bile Acids and Salts/metabolismABSTRACT
Cholesterol 7alpha-hydroxylase (CYP7A1) regulates the balance between cholesterol supply and metabolism by catalyzing the rate-limiting step of bile acid biosynthesis. The transcriptional activity of CYP7A1 is tightly controlled by various nuclear receptors. A forkhead transcription factor O1 (FOXO1) plays a critical role in metabolism, and insulin inactivates FOXO1 through Akt-dependent phosphorylation and nuclear exclusion. We investigated the role of insulin-Akt-FOXO1 signaling pathway in CYP7A1 transcriptional regulation since we found putative insulin-response elements, FOXO1 binding sequences, in both rat and human CYP7A1 promoters. However, ectopic expression of FOXO1 increased the rat CYP7A1-, but mildly reduced human CYP7A1-promoter activities in a dose-dependent manner. Similarly to bile acids, insulin treatment increased small heterodimer partner (SHP) mRNA rapidly and transiently, leading to the suppression of CYP7A1 transcription in both human and rodents. Chromatin immunoprecipitation showed that FOXO1 directly bound to rat CYP1A1 promoter in the absence of insulin. FOXO1 binding to the rat promoter was diminished by insulin treatment as well as by expression of SHP. Our results suggest that the stimulation of insulin- signaling pathway of Akt-FOXO1 and SHP expression may regulate cholesterol/bile acid metabolisms in liver, linking carbohydrate and cholesterol metabolic pathways. A prolonged exposure of insulin in hyperinsulinemic insulin resistance or diabetic status represses CYP7A1 transcription and bile acid biosynthesis through SHP induction and FOXO1 inactivation, leading to impairment of the hepatic cholesterol/bile acid metabolisms.
Subject(s)
Animals , Humans , Mice , Rats , Bile Acids and Salts/metabolism , Cholesterol/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , Forkhead Transcription Factors/genetics , Gene Expression Regulation/drug effects , Glucose/metabolism , Hep G2 Cells , Insulin/pharmacology , Lipid Metabolism/drug effects , Liver/metabolism , Mice, Inbred C57BL , Mutagenesis, Site-Directed , Nerve Tissue Proteins/genetics , Protein Binding/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Sequence Deletion/genetics , Signal Transduction/drug effects , Transcriptional Activation/drug effectsABSTRACT
Cholesterol 7alpha-hydroxylase (CYP7A1) regulates the balance between cholesterol supply and metabolism by catalyzing the rate-limiting step of bile acid biosynthesis. The transcriptional activity of CYP7A1 is tightly controlled by various nuclear receptors. A forkhead transcription factor O1 (FOXO1) plays a critical role in metabolism, and insulin inactivates FOXO1 through Akt-dependent phosphorylation and nuclear exclusion. We investigated the role of insulin-Akt-FOXO1 signaling pathway in CYP7A1 transcriptional regulation since we found putative insulin-response elements, FOXO1 binding sequences, in both rat and human CYP7A1 promoters. However, ectopic expression of FOXO1 increased the rat CYP7A1-, but mildly reduced human CYP7A1-promoter activities in a dose-dependent manner. Similarly to bile acids, insulin treatment increased small heterodimer partner (SHP) mRNA rapidly and transiently, leading to the suppression of CYP7A1 transcription in both human and rodents. Chromatin immunoprecipitation showed that FOXO1 directly bound to rat CYP1A1 promoter in the absence of insulin. FOXO1 binding to the rat promoter was diminished by insulin treatment as well as by expression of SHP. Our results suggest that the stimulation of insulin- signaling pathway of Akt-FOXO1 and SHP expression may regulate cholesterol/bile acid metabolisms in liver, linking carbohydrate and cholesterol metabolic pathways. A prolonged exposure of insulin in hyperinsulinemic insulin resistance or diabetic status represses CYP7A1 transcription and bile acid biosynthesis through SHP induction and FOXO1 inactivation, leading to impairment of the hepatic cholesterol/bile acid metabolisms.
Subject(s)
Animals , Humans , Mice , Rats , Bile Acids and Salts/metabolism , Cholesterol/metabolism , Cholesterol 7-alpha-Hydroxylase/genetics , Forkhead Transcription Factors/genetics , Gene Expression Regulation/drug effects , Glucose/metabolism , Hep G2 Cells , Insulin/pharmacology , Lipid Metabolism/drug effects , Liver/metabolism , Mice, Inbred C57BL , Mutagenesis, Site-Directed , Nerve Tissue Proteins/genetics , Protein Binding/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Sequence Deletion/genetics , Signal Transduction/drug effects , Transcriptional Activation/drug effectsABSTRACT
Insulin resistance is the basis of several common diseases, such as type 2 diabetes, affecting millions people worldwide and satisfactory treatments are limited. Therefore, it is important to understand the molecular mechanisms underlying this condition and to find new and more effective therapies. Bile acids may actively participate in the control of metabolism. They derive from cholesterol, and function as natural ligands of nuclear and membrane receptors, regulating gene expression and controlling their own metabolism and that of glucose, including insulin response. Moreover, bile acids have been related to endoplasmic reticulum stress, a cellular response tightly associated to insulin resistance. These features give bile acids pharmacological properties with potential therapeutic use. Herein, we discuss the physiological role of bile acids on glucose metabolism, particularly on the regulation of the insulin response.
Subject(s)
Humans , Bile Acids and Salts/metabolism , Glucose/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Insulin Resistance/physiology , Transcription FactorsABSTRACT
To analyze the expression of bile acid transport correlative proteins in the placenta of patients with intrahepatic cholestasis of pregnancy [ICP]. This case-control study was performed in the Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China from March 2007 to October 2008. Real time reverse transcriptase polymerase chain reaction was applied for the mRNA expression measurement of 8 bile acid transport correlative proteins, organic anion transporting polypeptide [OATP]1A2, OATP1B1, multidrug resistance protein [MRP]1, MRP2, anion exchanger [AE]2, bile salt export pump [BSEP], multidrug resistance 3, and familial intrahepatic cholestasis [FIC]1, in normal human placentas [n=20] and those with ICP [n=20]. All the transcripts except OATP1B1 and BSEP were detected. Both OATP1A2 and AE2 mRNA were higher while FIC1 was lower in ICP patients. The alteration of bile acid transport correlative proteins OATP1A2, AE2, and FIC1 may be involved in the fetal cholestasis of ICP
Subject(s)
Humans , Female , Bile Acids and Salts/metabolism , Gene Expression Regulation, Developmental , Multidrug Resistance-Associated Proteins/genetics , RNA, Messenger/analysis , ATP-Binding Cassette Transporters , Case-Control Studies , Placental CirculationABSTRACT
PURPOSE: To provide a systematic review with meta-analysis for addressing the relationship between fecal bile acids (FBAs) and colorectal cancer. MATERIALS AND METHODS: Electronic databases were searched for all observational studies that examined the relationship between FBAs and colorectal cancer or adenoma, and calculated weighted mean difference (WMD) and 95% confidence interval (CI). Publication bias was assessed with funnel plot. RESULTS: Twenty case-control or cohort studies were identified. All studies were pooled to assess the relationship between total FBAs and cancer/adenoma of the large bowel, however, no association was seen (WMD 0.61mg/g freeze-dried feces; 95% CI: -0.35-1.57). Significantly increased concentration of chenodeoxycholic acid (CDCA) was seen while pooling to assess the relationship between CDCA and cancer/adenoma of the large bowel (WMD 0.13 mg/g freeze-dried feces; 95% CI: 0.01-0.25), especially for colorectal cancer (WMD 0.28mg/g freeze-dried feces; 95% CI: 0.10-0.46). However, no significant differences in deoxycholic acid (DCA), lithocholic acid (LCA), and primary and secondary bile acids, were seen between patients with cancer and patients with matched controls regardless of fixed and random effects models. CONCLUSION: CDCA might play a role in the etiology of colorectal cancer.
Subject(s)
Female , Humans , Male , Bile Acids and Salts/metabolism , Carcinoma/etiology , Case-Control Studies , Cohort Studies , Colorectal Neoplasms/etiology , Feces/chemistryABSTRACT
Male albino rats were given ethanol (3.76 g/kg body weight/day) to induce hyperlipidemia. The rats showed increased concentration of cholesterol and triglycerides in the serum and tissues. Inclusion of coconut protein and L-arginine into ethanol fed rats produced lower levels of total cholesterol, LDL+ VLDL cholesterol, triglycerides and atherogenic index in the serum. Concentration of tissue cholesterol and triglycerides was also lower in these groups. Administration of coconut protein and L-arginine in the ethanol fed rats caused decreased activity of HMG-CoA reductase in the liver and increased activity of lipoprotein lipase in the heart. The activities of malic enzyme and glucose-6-phosphate dehydrogenase were also lower in these groups. Feeding coconut protein and L-arginine in ethanol treated rats showed increased concentration of hepatic bile acids and fecal excretion of neutral sterols and bile acids. All these effects were comparable in rats fed coconut protein and those fed L-arginine. These observations indicate that the major factor responsible for the hypolipidemic effect of coconut protein is due to the high content of L-arginine.
Subject(s)
Alcohols/pharmacology , Animals , Arginine/metabolism , Bile Acids and Salts/metabolism , Body Weight , Cholesterol/metabolism , Cocos/metabolism , Ethanol/pharmacology , Hydroxymethylglutaryl CoA Reductases/metabolism , Hyperlipidemias , Lipid Metabolism , Lipoproteins/metabolism , Liver/metabolism , Male , Organ Size , Plant Extracts/pharmacology , Rats , Rats, Sprague-Dawley , Triglycerides/metabolismABSTRACT
One month treatment of alloxan diabetic dogs with a glycoside, viz. leucopelargonin derivative (100 mg/kg/day) isolated from the bark of F. bengalensis decreased fasting blood sugar and glycosylated haemoglobin by 34% and 28% respectively. Body weight was maintained in both the treated groups while the same was decreased significantly by 10% in the control group. In cholesterol diet fed rats, as the atherogenic index and the hepatic bile acid level and the faecal excretion of bile acids and neutral sterols increased, the HMGCoA reductase and lipogenic enzyme activities in liver and lipoprotien lipase activity in heart and adipose tissue and plasma LCAT activity and the incorporation of labelled acetate into free and ester cholesterol in liver decreased significantly. On treatment with the two ficus flavonoids, viz. leucopelargonin and leucocyanin derivatives and another flavonoid quercetin (100 mg/kg/day) the above said effects except on bile acids and sterols and lipogenic enzymes were significantly reversed in the cholesterol fed rats. However in the treated rats the hepatic level of bile acids and the faecal excretion of bile acids and neutral sterols still further increased and the action of lipogenic enzyme glucose 6 phosphate dehydrogenase was still further decreased. These effects of leucopelargonidin and quercetin were better than that of the second. Toxicity studies are required to be carried out to find out if the ficus flavonoids could be used as health promoters as they are hypocholesterolemic and antioxidant in action.
Subject(s)
Animals , Anthocyanins/isolation & purification , Hypolipidemic Agents/therapeutic use , Arteriosclerosis/prevention & control , Bile Acids and Salts/metabolism , Blood Glucose/metabolism , Body Weight , Cholesterol, Dietary/administration & dosage , Diabetes Mellitus, Experimental/drug therapy , Dogs , Ficus/chemistry , Glycated Hemoglobin/metabolism , Liver/enzymology , Male , Rats , Rats, Sprague-DawleyABSTRACT
Epidemiological studies have shown a positive association between choloesterol gallstones and colonic cancer. These two diseases may be somehow related with bile acids metabolic alterations. The aim of this study was to evaluate the profiles of fecal bile acid in gallstone patients, in order to estimate the quality and amount of fecal bile acids. A fecal bile acid profile of ten gallstone patients and ten controls was compared using high performance liquid chromatography. Total fecal bile acid excretion was significantly increased in gallstone patients compared with controls (692.7 mg/day (302.5-846.2) vs 165.7 mg/day (138.7-221.3), p<0.01) as was the excretion of secondary free bile acids 562.9 mg/day (253.3-704.9) vs 99.9 mg/day (88.9-154.2), p<0.01). Lithocholic and glycodeoxycholic and percentages have also been found to show differences with controls of 55.4 (47.4-73.9) vs 24.6 (22.1-38.4) (p<0.01) and 29.4 (3.3-41.7) vs 2.8 (1.0-3.8) (p<0.03), respectively but deoxycholic acid has not shown differences between the two groups. Moreover, the percentage of ursodeoxycholic acid diminished significantly in gallstone patients (1.5 (1.0-2.8) vs 8.6 (6.0-10.39) (p<0.001), and the decrease of chenodeoxycholic acid was also significant (20.0 (11.4-23.6) vs 8.9 (3.1-10.9) (p<0.03) along with a rise in the rations lithocholic/deoxycholic acids (1.8 (1.4-6.4) vs 0.9 (0.6-1.6) (p<0.05) and glycine/taurine of deoxycholic acid (7.3 (4.1-46.6) vs 0.2 (0.1-0.5) (p<0.01). In conclusion, we have observed a significant increase of total and secondary fecal bile acid excretion as well as a rise of LCA and GDCA percentages and a rise in the ratios of LCA/DCA and glycinet/taurine of DCA.
Subject(s)
Humans , Male , Female , Middle Aged , Adult , Bile Acids and Salts/metabolism , Cholelithiasis/metabolism , Feces/chemistry , Analysis of Variance , Cholelithiasis/complications , Colonic Neoplasms/etiologyABSTRACT
Los ácidos biliares presentes en el contenido gástrico, productos de un reflujo duodeno gástrico han sido incriminados como responsables de agredir la mucosa gástrica mediante una acción detergente sobre la barrera defensiva. Esta acción nociva determina una lesión inflamatoria en dicha mucosa, constituyendo una gastritis crónica que se expresa clínicamente por dolor epigástrico pirosis y vómitos de aspecto biliosos entre otros síntomas, lo que ha constituido una entidad clínica llamada Gastritis Alcalina por Reflujo Duodenogástrico, más recientemente, Gastritis Reactiva según el Sistema Sydney. Las fibras dietéticas, más especialmente la celulosa, se han señalado como las más activas en la capacitación e inactivación de los ácidos biliares en recientes investigaciónes, lo que constituye una acción citoprotectora sobre la mucosa del estómago en los pacientes que presentan esta patología. En relación con estos conocimientos hemos realizado un estudio en 50 pacientes con gastritis alcalina diagnosticados por estudio endoscópico, dosificación de àcidos biliares totales en contenido gástrico y biopsia (excluyendo los pacientes con presencia de H. pylori); los cuales fueron divididos en 2 grupos de 25 cada uno, siendo tratados, el primer grupo (A) con almidón de maíz en polvo y el segundo grupo (B) con celulosa microcristalina en polvo a la dosis de 5 gramas diarios durante 3 meses observándose los seguientes resultados: los ácidos biliares totales en contenido gástrico disminuyeron al final del tratamiento de una forma mayoritaria en los pacientes tratados con microcelulosa, aunque no fue estadísticamente significativa. Desde el punto de vista clínico, hubo una respuesta altamente satisfactoria en el dolor, vómitos y pirosis al tratamiento con microcelulosa. Los signos endoscópicos inflamatorios localizados en la región antral y difusamente en toda la mucosa del estómago, mejoraron cuantitativamente, observándose, diferencia significativa en la localización antral. Los hallazgos histológicos al final del tratamiento, en el grupo A y en el grupo B no mostraron variaciones evolutivas en el estudio comparativo de las lesiones encontradas al inicio del tratamiento. Los resultados se muestran en tablas.
Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Bile Acids and Salts/metabolism , Bile Reflux/complications , Cellulose/pharmacology , Gastric Mucosa/drug effects , Gastritis/etiology , Bile Acids and Salts/analysis , Cellulose/administration & dosage , Cellulose/therapeutic use , Crystallization , Gastritis/drug therapy , Prospective StudiesABSTRACT
The colorectal neoplasia is the second cause of death from neoplasia in our country, and in international statistics, blaming forthis, the dietetic habits of industrialized countries having a high content of satured fat, cholesterol, refined carbohydrate, red meat, and with few dietetic fibers. In the last years special attention has been focused to the action of the total biliar acids (TBA) primarily the secondary ones, over the colon mucosa, showing evidences of cancerous effects. Recently, American authors have published the favoring action of the cellulose fiber over the TBA through a catalytic reaction and their polysterification, inactivating them in their aggressive action over the colon mucosa. Through these experiences and willing to prove the action of the product, we have treated with mycrocristalline cellulosa (Microcel Lab. Blanver, Brasil) 20 patients of the Institute of Gastroenterology of Havana City, who showed high figures of TBA in stools for 2 months, compared with the 5 g. dose per day. Another group of 20 patients also with high figures of TBA in stools being treated with corn fecula same dose, same time by equal time. making every month determinations to both groups, determinig that in the first group the figures of TBA in stools were normalized in 95 per cent the first month of treatment and in 100 per cent the second month. The second group had only an answer of 65 per cent the first month and of 80 per cent the second month, which shows evidently the high efficacy of Microcel in reducing the TBA in stools.