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1.
Gene ; 725: 144167, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639434

RESUMO

Osteoporosis in advanced cholestatic and end-stage liver disease is related to low bone formation. Previous studies have demonstrated the deleterious consequences of lithocholic acid (LCA) and bilirubin on osteoblastic cells. These effects are partially or completely neutralized by ursodeoxycholic acid (UDCA). We have assessed the differential gene expression of osteoblastic cells under different culture conditions. The experiments were performed in human osteosarcoma cells (Saos-2) cultured with LCA (10 µM), bilirubin (50 µM) or UDCA (10 and 100 µM) at 2 and 24 h. Expression of 87 genes related to bone metabolism and other signalling pathways were assessed by TaqMan micro fluidic cards. Several genes were up-regulated by LCA, most of them pro-apoptotic (BAX, BCL10, BCL2L13, BCL2L14), but also MGP (matrix Gla protein), BGLAP (osteocalcin), SPP1 (osteopontin) and CYP24A1, and down-regulated bone morphogenic protein genes (BMP3 and BMP4) and DKK1 (Dickkopf-related protein 1). Parallel effects were observed with bilirubin, which up-regulated apoptotic genes and CSF2 (colony-stimulating factor 2) and down-regulated antiapoptotic genes (BCL2 and BCL2L1), BMP3, BMP4 and RUNX2. UDCA 100 µM had specific consequences since differential expression was observed, up-regulating BMP2, BMP4, BMP7, CALCR (calcitonin receptor), SPOCK3 (osteonectin), BGLAP (osteocalcin) and SPP1 (osteopontin), and down-regulating pro-apoptotic genes. Furthermore, most of the differential expression changes induced by both LCA and bilirubin were partially or completely neutralized by UDCA. Conclusion: Our observations reveal novel target genes, whose regulation by retained substances of cholestasis may provide additional insights into the pathogenesis of osteoporosis in cholestatic and end-stage liver diseases.


Assuntos
Bilirrubina/metabolismo , Osteoblastos/metabolismo , Osteoporose/genética , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/metabolismo , Linhagem Celular Tumoral , Colestase/genética , Regulação para Baixo/efeitos dos fármacos , Perfil Genético , Humanos , Ácido Litocólico/farmacologia , Fígado/metabolismo , Fígado/fisiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Osteoporose/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido Ursodesoxicólico/farmacologia
2.
Gut ; 69(1): 146-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723104

RESUMO

OBJECTIVE: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. DESIGN: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. RESULTS: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. CONCLUSION: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.


Assuntos
Sistema Biliar/fisiopatologia , Colestase Intra-Hepática/prevenção & controle , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Colestase Intra-Hepática/metabolismo , Impedância Elétrica , Epitélio/fisiopatologia , Ácidos Isonipecóticos/farmacologia , Ácidos Isonipecóticos/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oximas/farmacologia , Oximas/uso terapêutico , Permeabilidade , Fosforilação/fisiologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais/fisiologia , Proteínas de Junções Íntimas/metabolismo
3.
J Agric Food Chem ; 67(48): 13307-13317, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31679333

RESUMO

Epidemiological studies have demonstrated that hypercholesterolemia is associated with an elevated risk of atherosclerosis and cardiovascular diseases. In addition to the available cholesterol-lowering drugs, nutritionally balanced diets containing functional foods have attracted much interest as potential candidates to improve hypercholesterolemia. In the study, we demonstrated that dietary succinoglycan riclin effectively alleviated diet-induced hypercholesterolemia. Compared with the high-cholesterol-diet (HCD) group, the high-riclin group significantly decreased levels of the serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and hepatic cholesterol (34, 40, and 51%, respectively), consequently improving hepatic steatosis and reducing proinflammatory cytokine expressions. 1H nuclear magnetic resonance (NMR)-based lipidomics and metabolomics analyses revealed that the riclin group partially reversed metabolic profile changes induced by the HCD, approaching that of the normal diet (ND) group. Riclin has no direct effects on cholesterol metabolism-related gene expression among the three HCD model groups. Basically, riclin increased the solution viscosity and interfered in the process of bile acid-cholesterol emulsification, decreasing cholesterol digestion and promoting cholesterol and bile acid excretion in the feces. These results suggested potential therapeutic utility of succinoglycan riclin as a food additive for people suffering from hypercholesterolemia and related diseases.


Assuntos
Anticolesterolemiantes/metabolismo , Hipercolesterolemia/dietoterapia , Polissacarídeos Bacterianos/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
J Agric Food Chem ; 67(38): 10614-10623, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31483658

RESUMO

Type 2 diabetes (T2D) is a pandemic disease chiefly characterized by hyperglycemia. In this study, the combination of serum lipidomic and metabolomic approach was employed to investigate the effect of arabinoxylan on type 2 diabetic rats and identify the critical biomarkers of T2D. Metabolomics analysis revealed that branched-chain amino acids, 12α-hydroxylated bile acids, ketone bodies, and several short- and long-chain acylcarnitines were significantly increased in T2D, whereas lysophosphatidylcholines (LPCs) were significantly decreased. Lipidomics analysis indicated T2D-related dyslipidemia was mainly associated with the increased levels of acetylcarnitine, free fatty acids (FFA), diacylglycerols, triacylglycerols, and cholesteryl esters and the decreased levels of some unsaturated phosphatidylcholines (less than 22 carbons). These variations indicated the disturbed amino acid and lipid metabolism in T2D, and the accumulation of incompletely oxidized lipid species might eventually contribute to impaired insulin action and glucose homeostasis. Arabinoxylan treatment decreased the concentrations of 12α-hydroxylated bile acids, carnitines, and FFAs and increased the levels of LPCs. The improved bile acid and lipid metabolism by arabinoxylan might be involved in the alleviation of hypercholesterolemia and hyperlipidemia in T2D.


Assuntos
Anticolesterolemiantes/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Xilanos/administração & dosagem , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Carnitina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos , Lipídeos/química , Metabolômica , Ratos
6.
Nat Med ; 25(9): 1442-1452, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477907

RESUMO

Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used 'omics' survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.


Assuntos
Bactérias/genética , Microbioma Gastrointestinal/genética , Filogenia , Seleção Genética/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Ácidos e Sais Biliares/genética , Ácidos e Sais Biliares/metabolismo , Bancos de Espécimes Biológicos , Fezes/microbiologia , Variação Genética/genética , Genoma Bacteriano/genética , Humanos , Metaboloma/genética
7.
Cell Mol Life Sci ; 76(24): 4849-4859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31407019

RESUMO

The farnesoid-X-receptorα (FXRα; NR1H4) is one of the main bile acid (BA) receptors. During the last decades, through the use of pharmalogical approaches and transgenic mouse models, it has been demonstrated that the nuclear receptor FXRα controls numerous physiological functions such as glucose or energy metabolisms. It is also involved in the etiology or the development of several pathologies. Here, we will review the unexpected roles of FXRα on the male reproductive tract. FXRα has been demonstrated to play functions in the regulation of testicular and prostate homeostasis. Even though additional studies are needed to confirm these findings in humans, the reviewed reports open new field of research to better define the effects of bile acid-FXRα signaling pathways on fertility disorders and cancers.


Assuntos
Genitália Masculina/crescimento & desenvolvimento , Próstata/crescimento & desenvolvimento , Receptores Citoplasmáticos e Nucleares/genética , Testículo/crescimento & desenvolvimento , Animais , Ácidos e Sais Biliares/metabolismo , Genitália Masculina/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Próstata/metabolismo , Transdução de Sinais/genética , Testículo/metabolismo , Fatores de Transcrição/genética
8.
J Anim Sci ; 97(10): 4235-4241, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31430375

RESUMO

The objective of this study was to investigate the effects of diets supplemented with sodium stearoyl-2-lactylate (SSL), polyglycerol fatty acid ester (PGFE), and combined emulsifiers (0.02% SSL and 0.08% PGFE) on growth performance, nutrient digestibility, and plasma lipid profiles in weaned piglets and to further evaluate the possible effects of feeding exogenous emulsifiers on digestive enzyme activities and liver bile acid (BA) metabolism. Twenty-eight barrows (age at 35 d, Duroc × Landrace × Yorkshire) with an initial BW of 10.13 ± 0.16 kg were randomly assigned to 4 dietary treatment groups (7 pigs/treatment). Dietary treatment groups included the following: 1) basal diet (Control, CTR); 2) basal diet with 0.1% SSL (SSL); 3) basal diet with 0.1% PGFE (PGFE); and 4) basal diet with 0.08% PGFE+0.02% SSL (PG-SL). SSL diet increased ADG and ADFI of piglets during day 0 to 17 (P < 0.05) compared with the CTR treatment. Piglets fed emulsifier diets experienced a significant improvement in the digestibility of nutrients (DM, CP, ether extract, energy, calcium, and phosphorus) during the first 17 d (P < 0.05). The level of low-density lipoprotein cholesterol (LDL-C) was lower in the PGFE and PG-SL treatment groups than in the CTR treatment group (P < 0.05). Feeding emulsifier diets increased the lipase activity of the pancreas when compared with the CTR diet (P < 0.05). Moreover, the emulsifier diets significantly increased the mRNA expression of FXR (P < 0.05) and decreased the mRNA expression of CYP27A1 (P < 0.05) in the liver. In conclusion, the addition of emulsifiers improved nutrient digestibility and increased the mRNA expression of FXR BA receptors while inhibiting the mRNA expression of BA biosynthesis by CYP27A1 in weanling piglets.


Assuntos
Ração Animal/análise , Suplementos Nutricionais/análise , Ácidos Graxos/administração & dosagem , Estearatos/administração & dosagem , Suínos/fisiologia , Animais , Ácidos e Sais Biliares/metabolismo , Dieta/veterinária , Digestão , Emulsificantes/administração & dosagem , Feminino , Masculino , Nutrientes , Distribuição Aleatória , Suínos/crescimento & desenvolvimento , Desmame
9.
PLoS Genet ; 15(8): e1008073, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31465442

RESUMO

The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.


Assuntos
Ácidos e Sais Biliares/metabolismo , Variação Biológica da População/genética , Microbioma Gastrointestinal/fisiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Locos de Características Quantitativas/genética , Simportadores/genética , Animais , Ácidos e Sais Biliares/sangue , Camundongos de Cruzamento Colaborativo , Feminino , Firmicutes/crescimento & desenvolvimento , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Modelos Animais , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Verrucomicrobia/crescimento & desenvolvimento
10.
Environ Pollut ; 254(Pt B): 113052, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31465901

RESUMO

In our study, Bufo gargarizans (B. gargarizans) larvae were exposed to control, 0.5, 5, 10 and 50 mg/L of NaF from Gs 26 to 42. At Gs 42, we evaluated the changes of liver histology and the mRNA levels of target genes in liver. In addition, we also examined the composition and content of fatty acids. Histological analysis revealed that fluoride caused liver injury, such as the increase of number of melanomacrophage centres, atrophy of nucleus, dilation of bile canaliculus, and decrease of quantity, degradation and deposition of lipid droplets. The results of RT-qPCR indicated that exposure to 5, 10 and 50 mg/L of NaF significantly decreased the transcript levels of genes related to fatty acid synthesis (FASN, FAE, MECR, KAR and TECR) in liver. Besides, mRNA expression of genes involved in fatty acid ß-oxidation (ECHS1, HADHA, SCP2, CPT2, ACAA1 and ACAA2) and oxidative stress (SOD, GPx, MICU1 and HSP90) was significantly downregulated in 0.5, 5, 10 and 50 mg/L of NaF treatment groups. Also, in the relative expression of genes associated with synthesis and secretion of bile acid, BSEP significantly increased at 0.5, 5 and 50 mg/L of NaF while HSD3B7 significantly reduced in 0.5, 5, 10 and 50 mg/L of NaF. Finally, the fatty acid extraction and GC-MS analysis showed that the content of saturated fatty acids (SFAs) was decreased and the content of polyunsaturated fatty acids (PUFAs) was increased in all fluoride treatment groups. Taken together, the present results indicated that fluoride-induced the histological alterations of liver might be linked to the disorder of lipid metabolism, oxidative damage.


Assuntos
Bufonidae/fisiologia , Fluoretos/toxicidade , Animais , Ácidos e Sais Biliares/metabolismo , Fluoretos/metabolismo , Larva/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo
11.
J Therm Biol ; 84: 375-383, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31466777

RESUMO

Bile acids (BAs) are critical for cholesterol homeostasis and new roles in metabolism and endocrinology have been demonstrated recently. It remains unknown whether BA metabolism can be affected by heat stress (HS). The objective of this study was to describe the shifts in serum, hepatic and intestinal BA profiles induced by chronic HS. Twenty-seven Large White pigs weighing 40.8 ±â€¯2.7 kg were assigned to one of the three treatments: a control group (CON, 23 °C), a HS group (33 °C), or a pair-fed group (PF, 23 °C and fed the same amount as HS group) for 21 d. The concentrations of taurine-conjugated BAs (TUDCA and THDCA in serum and TCDCA, TUDCA, THDCA and THCA in liver) were decreased in HS and PF pigs. However, in HS pigs, a reduction in taurine-conjugated BAs (TCBA) correlated with decreased liver genes expression of BA synthesis, conjugation and uptake transport. BA regulated-genes (FXR, TGR5 and FGFR4) in HS pigs and TGR5, FGFR4 and KLß in PF pigs were down-regulated in liver. In ileum, total BAs and glycoursodeoxycholic acid concentrations were higher in HS pigs than other groups and PF group, respectively (P < 0.05). TCBA (P = 0.01) and tauroursodeoxycholic acid (P < 0.01) were decreased in PF group. BA transporters (OSTα and MRP3) were up-regulated in HS pigs compared with CON and PF pigs, respectively (P < 0.01). In cecum, ursodeoxycholic acid was higher in HS (P = 0.02) group than CON group. The expression of apical sodium-coupled bile acid transporter (P = 0.04) was lower in HS pigs than CON pigs, while OSTß (P < 0.01) was greater in HS group than PF group. These results suggest that chronic HS suppressed liver activity of synthesis and uptake of TCBA, at least in part, which was independent of reduced feed intake.


Assuntos
Ácidos e Sais Biliares/metabolismo , Transtornos de Estresse por Calor/metabolismo , Doenças dos Suínos/metabolismo , Suínos/metabolismo , Animais , Ácidos e Sais Biliares/sangue , Conteúdo Gastrointestinal/química , Conteúdo Gastrointestinal/microbiologia , Transtornos de Estresse por Calor/veterinária , Resposta ao Choque Térmico , Temperatura Alta , Fígado/metabolismo , Masculino
12.
J Agric Food Chem ; 67(34): 9543-9550, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31379164

RESUMO

This study aimed to reveal the mechanisms underlying the interaction between condensed tannins (CTs) and bile salts. The interaction mechanism was analyzed by transmission electron microscopy, exposure to various physicochemical conditions, electrophoresis, fluorescence spectroscopy, isothermal titration calorimetry, and molecular modeling. A new complex was formed from CTs and bile salts. The complex showed a negative enthalpy change and a positive entropy change, demonstrating that the main thermodynamic driving force was both entropy and enthalpy and indicating that binding occurred through hydrogen bonds and hydrophobic interactions. The analysis of the effects of CTs on the stability and digestion properties of bile salt emulsions indicated that CTs were able to inhibit lipid digestion to an extent. Our findings may provide evidence that foods rich in CTs offer health benefits by aggregating with bile salts and reducing the absorption of fat.


Assuntos
Ácidos e Sais Biliares/química , Proantocianidinas/química , Ácidos e Sais Biliares/metabolismo , Calorimetria , Emulsões/química , Emulsões/metabolismo , Entropia , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Proantocianidinas/metabolismo , Termodinâmica
13.
Curr Protein Pept Sci ; 20(10): 976-983, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31362653

RESUMO

Diabetes mellitus (DM) has become an increasingly common disease with high disability and mortality rates. Diabetes complications are the main cause of diabetes death and about 50% of diabetic patients died from heart disease in developed countries reported by World Health Organization. Diabetic cardiomyopathy (DCM) has been considered as a high incidence and serious complication of DM and plays a key role in the incidence and development of diabetes related heart failure. Metabolism dysregulation is regarded as an important and earlier factor occurred in the pathogenesis of DCM. Insulin resistance, oxidative stress, inflammation and mitochondrial dysfunction also contribute to the development of DCM. Farnesoid X Receptor (FXR) is a member of nuclear receptor superfamily, and plays a critical role in regulating lipid and glucose metabolism, oxidative stress and inflammation. FXR is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid and synthetic agonists such as obeticholic acid. BAs are the main active ingredients of many natural products and traditional medicines, especially bile or gallstones in animals, such as calculus bovis. Due to the regulatory effect of FXR on glucose and lipid metabolism, oxidative stress and inflammation, the treatment of BAs and FXR agonists for metabolic syndrome and DCM have gained more attention. This review will focus on the pathogenesis of diabetic cardiomyopathy and the regulatory effect of BAs and FXR on DCM.


Assuntos
Ácidos e Sais Biliares/metabolismo , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Biomarcadores/metabolismo , Glucose/metabolismo , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos
14.
Int J Mol Sci ; 20(17)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443432

RESUMO

Placenta performs the function of several adult organs for the fetus during intrauterine life. Because of the dramatic physiological and metabolic changes during pregnancy and the strong association between maternal metabolism and placental function, the possibility that variation in gene expression patterns during pregnancy might be linked to fetal health warrants investigation. Here, next-generation RNA sequencing was used to investigate the expression profile, including mRNAs and long non-coding RNAs (lncRNAs) of placentas on day 60 of gestation (G60), day 90 of gestation (G90), and on the farrowing day (L0) in pregnant swine. Bioinformatics analysis of differentially expressed mRNAs and lncRNAs consistently showed dysregulation of bile acids transport and detoxification as pregnancy progress. We found the differentially expressed mRNAs, particularly bile salt export pump (ABCB11), organic anion-transporting polypeptide 1A2 (OATP1A2), carbonic anhydrase II (CA2), Na+-HCO3- cotransporter (NBC1), and hydroxysteroid sulfotransferases (SULT2A1) play an important role in bile acids transport and sulfation in placentas during pregnancy. We also found the potential regulation role of ALDBSSCG0000000220 and XLOC_1301271 on placental SULT2A1. These findings have uncovered a previously unclear function and its genetic basis for bile acids metabolism in developing placentas and have important implications for exploring the potential physiological and pathological pathway to improve fetal outcomes.


Assuntos
Ácidos e Sais Biliares/metabolismo , Inativação Metabólica , Placenta/metabolismo , Transcriptoma , Animais , Transporte Biológico , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Gravidez , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Suínos
15.
Biol Pharm Bull ; 42(8): 1366-1375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366871

RESUMO

Drug-induced liver injury (DILI) is a common side effect of several medications and is considered a major factor responsible for the discontinuation of drugs during their development. Cholestasis is a DILI that results from impairment of bile acid transporters, such as the bile salt export pump (BSEP), leading to accumulation of bile acids. Both in vitro and in vivo studies are required to predict the risk of drug-induced cholestasis. In the present study, we used chimeric mice with humanized liver as a model to study drug-induced cholestasis. Administration of a single dose of ketoconazole or rifampicin, known to potentially cause cholestasis by inhibiting BSEP, did not result in elevated levels of alkaline phosphatase (ALP), which are known hepatic biomarkers. The concentration of taurodeoxycholic acid increased in the liver after ketoconazole administration, whereas rifampicin resulted in increased tauromuricholic acid and taurocholic acid (TCA) levels in the liver and plasma. Furthermore, rifampicin resulted in an increase in the uniform distribution of a compound with m/z 514.3, presumed as TCA through imaging mass spectrometry. The mRNA levels of bile acid-related genes were also altered after treatment with ketoconazole or rifampicin. We believe these observations to be a part of a feedback mechanism to decrease bile acid concentrations. The changes in bile acid concentrations results may reflect the initial responses of the human body to cholestasis. Furthermore, these findings may contribute to the screening of drug candidates, thereby avoiding drug-induced cholestasis during clinical trials and drug development.


Assuntos
Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colestase/metabolismo , Cetoconazol/efeitos adversos , Fígado/efeitos dos fármacos , Rifampina/efeitos adversos , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Ácidos e Sais Biliares/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Colestase/sangue , Colestase/induzido quimicamente , Humanos , Cetoconazol/sangue , Cetoconazol/farmacocinética , Fígado/metabolismo , Masculino , Camundongos , Rifampina/sangue , Rifampina/farmacocinética
16.
Physiol Biochem Zool ; 92(5): 463-472, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31368840

RESUMO

Pheromones are important sexual signals in most animals, but research into their evolution is largely biased toward insects. Lampreys are a jawless fish with a relatively well-understood pheromone communication system, and they offer a useful opportunity to study pheromone evolution in a vertebrate. Once sexually mature, male sea lamprey (Petromyzon marinus) and likely other lampreys produce and release bile acids that act as sex pheromones. Spawning males do not feed and therefore produce bile acids primarily for sexual communication, whereas larvae produce the same bile acids but for digestion, offering an opportunity to compare the evolution of bile acids produced for sexual versus nonsexual functions. We profiled eight pheromone-related bile acids in livers from larvae and males and determined the effect of life stage on intra- and interspecific variation in bile acid production. Our results indicate less variation among males than larvae within P. marinus but more variation among species for males than larvae. We postulate that bile acid production in males is shaped by directional or stabilizing selection that reduces variance within P. marinus and directional or disruptive selection that promotes diversification across species. Although our results offer support for the role of sexual selection in the evolution of lamprey pheromones, they do not eliminate possible roles of other aspects of lamprey ecology.


Assuntos
Ácidos e Sais Biliares/metabolismo , Lampreias/fisiologia , Atrativos Sexuais/metabolismo , Animais , Masculino , Reprodução/fisiologia , Especificidade da Espécie
17.
Nat Med ; 25(8): 1225-1233, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31332392

RESUMO

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.


Assuntos
Ácidos e Sais Biliares/metabolismo , Fator de Transcrição GATA3/fisiologia , Microbioma Gastrointestinal , Interleucinas/fisiologia , Síndrome do Ovário Policístico/etiologia , Animais , Feminino , Humanos , Inflamação/complicações , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , Ovário/fisiopatologia , Síndrome do Ovário Policístico/fisiopatologia
18.
Life Sci ; 232: 116638, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31288013

RESUMO

AIMS: High-fat diet (HFD)-induced obesity resulting in cholesterol accumulation is one of the common pathogenic factors for lipids metabolic disorders. However, the potential mechanisms about cholesterol accumulation during obesity are still not clearly identified. Bile acids (BAs) as the natural ligands of farnesoid x receptor (Fxr) are demonstrated that can regulate the relevant enzymes and transporters at transcriptional level to determine the cholesterol homeostasis. Here, we explored the underlying mechanisms of hepatic cholesterol accumulation in HFD-induced obesity rats via the BAs-Fxr-enzymes/transporters signaling pathways. MATERIALS AND METHODS: BAs and cholesterol levels as well as mRNA expressions of enzymes, transporters and nuclear receptors involving in cholesterol homeostasis in liver and ileum tissue were evaluated in 4-week HFD-induced obesity rats. KEY FINDINGS: HFD promoted BAs intestine passive absorption to increase the concentrations of BAs especially the chenodeoxycholic acids (CDCAs) in ileum of HFD-induced obesity rats. The increased CDCAs concentrations activated Fxr-Fgf15 pathway in ileum to result in the mRNA expression of Cyp7a1 in liver down-regulation, which inhibited cholesterol metabolizing into primary BAs to contribute to the cholesterol level increase in liver tissue in HFD-induced obesity rats. SIGNIFICANCE: The hepatic cholesterol accumulation should be ascribed to the activation of ileum Fxr-Fgf15 pathway by the increased BAs passive absorption into ileal enterocytes under the condition of rats fed with HFD, which inhibited hepatic Cyp7a1 gene transcription to reduce metabolic elimination of cholesterol. Moreover, these findings are expected to provide a cue for the treatment of cholesterol metabolism disorders in obesity patient.


Assuntos
Colesterol 7-alfa-Hidroxilase/antagonistas & inibidores , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/metabolismo , Íleo/metabolismo , Fígado/metabolismo , Obesidade/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Células CACO-2 , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/metabolismo , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Obesidade/enzimologia , Ratos , Ratos Wistar , Transdução de Sinais
19.
Life Sci ; 232: 116643, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299237

RESUMO

AIMS: Increased plasma soluble endoglin concentrations (sEng) are frequently detected in metabolic disorders accompanied with hypercholesterolemia in serum, but effect of sEng on the cholesterol biochemistry is unknown. Cholesterol and bile acids (BA) are important products of liver metabolism with numerous functions within the organism. Turnover of these substances requires precise regulation due to potential toxicities during their cumulation. In this study, we hypothesized that high sEng levels affect cholesterol homeostasis and BA turnover in mice liver. MAIN METHODS: Nine-month-old transgenic male mice overexpressing human sEng and wild-type mice underwent plasma, bile, stool, and organ samples analysis by analytical, qRT-PCT and Western blot methods. KEY FINDINGS: sEng mice demonstrated decreased plasma total and LDL cholesterol concentrations due to upregulation of hepatic Sr-b1 and Ldlr receptors, increased liver cholesterol content, and increased Abcg8-mediated cholesterol efflux into bile. sEng also increased conversion of cholesterol into bile acids (BA) via upregulation of Cyp7a1 and increased Mdr1 expression. Plasma concentrations of BA were increased in sEng mice due to their enhanced reabsorption via ileum. Increased hepatic disposition of BA led to their increased biliary excretion coupled with choleretic activity. SIGNIFICANCE: For the first time, we have shown that high sEng plasma levels affect cholesterol and BA homeostasis on the basis of complex liver and intestinal effects. The significance of these findings for pathophysiology of diseases associated with increased sEng concentrations remains to be elucidated in prospective studies.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Endoglina/sangue , Endoglina/fisiologia , Homeostase , Fígado/metabolismo , Animais , Ácidos e Sais Biliares/sangue , Colesterol/sangue , Fezes , Inflamação/sangue , Masculino , Camundongos , Camundongos Transgênicos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Estresse Oxidativo , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Simportadores/metabolismo , Regulação para Cima
20.
Eur J Pharm Biopharm ; 141: 191-209, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31150808

RESUMO

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies. In this work, we detail the development and application of the Simcyp canine ADAM model to nine danazol oral formulations and compare the model predictions to caninein vivo pharmacokinetic data from published literature. The application of this mechanistic approach revealed insights suggesting: (1) complete danazol solubilization in vitro may lead to an over-estimation of oral bioavailability when predictions are not corrected for the in vivo conditions promoting gut luminal precipitation; (2) some solubilizing excipients can influence intestinal physiology in a manner that may reduce danazol absorption; (3) danazol-formulation-luminal bile salts interplay can result in the formation of mixed micelles that negatively impact danazol intestinal permeability; and (4) the magnitude of danazol bioavailability enhancement associated with the use of solubilizing agents can be affected by the presence of saturable gut metabolism that can lead to concentration-dependent differences in its influence in vivo formulation behaviour at high versus low doses.


Assuntos
Danazol/farmacocinética , Jejum/metabolismo , Mucosa Intestinal/metabolismo , Administração Oral , Animais , Ácidos e Sais Biliares/metabolismo , Disponibilidade Biológica , Química Farmacêutica/métodos , Cães , Excipientes/química , Absorção Intestinal/efeitos dos fármacos , Intestinos , Modelos Biológicos , Permeabilidade/efeitos dos fármacos , Fenômenos Físicos , Solubilidade/efeitos dos fármacos
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