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Systemic bile acids induce insulin resistance in a TGR5-independent manner.
Syring KE, Cyphert TJ, Beck TC, Flynn CR, Mignemi NA, McGuinness OP
(2019) Am J Physiol Endocrinol Metab 316: E782-E793
MeSH Terms: Animals, Bile Acids and Salts, Cholagogues and Choleretics, Cholic Acids, Deoxycholic Acid, Gene Expression Profiling, Gluconeogenesis, Glucose Clamp Technique, Hep G2 Cells, Hepatocytes, Humans, Insulin Resistance, Liver, Mice, Mice, Knockout, Obesity, Primary Cell Culture, Receptors, G-Protein-Coupled, Taurocholic Acid
Show Abstract · Added April 15, 2019
Bile acids are involved in the emulsification and absorption of dietary fats, as well as acting as signaling molecules. Recently, bile acid signaling through farnesoid X receptor and G protein-coupled bile acid receptor (TGR5) has been reported to elicit changes in not only bile acid synthesis but also metabolic processes, including the alteration of gluconeogenic gene expression and energy expenditure. A role for bile acids in glucose metabolism is also supported by a correlation between changes in the metabolic state of patients (i.e., obesity or postbariatric surgery) and altered serum bile acid levels. However, despite evidence for a role for bile acids during metabolically challenging settings, the direct effect of elevated bile acids on insulin action in the absence of metabolic disease has yet to be investigated. The present study examines the impact of acutely elevated plasma bile acid levels on insulin sensitivity using hyperinsulinemic-euglycemic clamps. In wild-type mice, elevated bile acids impair hepatic insulin sensitivity by blunting the insulin suppression of hepatic glucose production. The impaired hepatic insulin sensitivity could not be attributed to TGR5 signaling, as TGR5 knockout mice exhibited a similar inhibition of insulin suppression of hepatic glucose production. Canonical insulin signaling pathways, such as hepatic PKB (or Akt) activation, were not perturbed in these animals. Interestingly, bile acid infusion directly into the portal vein did not result in an impairment in hepatic insulin sensitivity. Overall, the data indicate that acute increases in circulating bile acids in lean mice impair hepatic insulin sensitivity via an indirect mechanism.
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19 MeSH Terms
Associations between circulating 1,25(OH)₂D concentration and odds of metachronous colorectal adenoma.
Hibler EA, Molmenti CL, Lance P, Jurutka PW, Jacobs ET
(2014) Cancer Causes Control 25: 809-17
MeSH Terms: Adenoma, Adult, Aged, Aged, 80 and over, Calcitriol, Cholagogues and Choleretics, Colorectal Neoplasms, Double-Blind Method, Female, Humans, Male, Middle Aged, Odds Ratio, Risk Factors, Ursodeoxycholic Acid
Show Abstract · Added December 29, 2014
Cellular-level studies demonstrate that the availability of the secosteroid hormone 1α,25-dihydroxyvitamin D [1,25(OH)2D] to colon cells promotes anti-carcinogenic activities. Although epidemiological data are relatively sparse, suggestive inverse trends have been reported between circulating 1,25(OH)2D concentration and colorectal neoplasia. We therefore sought to evaluate the relationship between circulating 1,25(OH)2D concentrations and odds for metachronous colorectal adenomas among 1,151 participants from a randomized trial of ursodeoxycholic acid for colorectal adenoma prevention. No relationship between 1,25(OH)2D and overall odds for metachronous lesions was observed, with ORs (95% CIs) of 0.80 (0.60-1.07) and 0.81 (0.60-1.10) for participants in the second and third tertiles, respectively, compared with those in the lowest (p-trend = 0.17). However, a statistically significant inverse association was observed between circulating 1,25(OH)2D concentration and odds of proximal metachronous adenoma, with an OR (95% CI) of 0.71 (0.52-0.98) for individuals in the highest tertile of 1,25(OH)2D compared with those in the lowest (p-trend = 0.04). While there was no relationship overall between 1,25(OH)2D and metachronous distal lesions, there was a significantly reduced odds for women, but not men, in the highest 1,25(OH)2D tertile compared with the lowest (OR 0.53; 95% CI 0.27-1.03; p-trend = 0.05; p-interaction = 0.08). The observed differences in associations with proximal and distal adenomas could indicate that delivery and activity of vitamin D metabolites in different anatomic sites in the colorectum varies, particularly by gender. These results identify novel associations between 1,25(OH)2D and metachronous proximal and distal colorectal adenoma, and suggest that future studies are needed to ascertain potential mechanistic differences in 1,25(OH)2D action in the colorectum.
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Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids.
Nagathihalli NS, Beesetty Y, Lee W, Washington MK, Chen X, Lockhart AC, Merchant NB
(2014) Cancer Res 74: 2062-72
MeSH Terms: ADAM Proteins, ADAM17 Protein, Amphiregulin, Bile Acids and Salts, Cyclin D1, Deoxycholic Acid, EGF Family of Proteins, ErbB Receptors, Gastrointestinal Neoplasms, Glycoproteins, HCT116 Cells, Humans, Intercellular Signaling Peptides and Proteins, Pancreas, Phosphorylation, Receptors, G-Protein-Coupled, STAT3 Transcription Factor, Transforming Growth Factor alpha, src-Family Kinases
Show Abstract · Added February 14, 2014
Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both colorectal cancer and PDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment.
©2014 AACR.
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19 MeSH Terms
Associations between vitamin D-binding protein isotypes, circulating 25(OH)D levels, and vitamin D metabolite uptake in colon cancer cells.
Hibler EA, Jacobs ET, Stone AD, Sardo CL, Galligan MA, Jurutka PW
(2014) Cancer Prev Res (Phila) 7: 426-34
MeSH Terms: Adult, Aged, Aged, 80 and over, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, DNA, Neoplasm, Double-Blind Method, Female, Genotype, Humans, Male, Middle Aged, Protein Isoforms, Randomized Controlled Trials as Topic, Real-Time Polymerase Chain Reaction, Receptors, Calcitriol, Tumor Cells, Cultured, Ursodeoxycholic Acid, Vitamin D, Vitamin D-Binding Protein
Show Abstract · Added December 29, 2014
Vitamin D metabolites have been extensively studied as cancer chemopreventive agents. Gc-globulin (GC) isotypes, based on rs7041 and rs4588 diplotypes, have varying affinities for 1α,25-dihydroxyvitamin D (1,25(OH)2D) and 25-hydroxyvitamin D (25(OH)D), which may affect circulating metabolite concentration as well as delivery at the cellular level. We evaluated associations between GC isotype and circulating vitamin D metabolite concentrations in 403 ursodeoxycholic acid (UDCA) clinical trial participants. Metabolite uptake was evaluated in human colon cancer (HCT-116) cells treated with ethanol vehicle, 1,25(OH)2D, or 25(OH)D, and with plasma from individuals with known GC isotype. Mammalian-2-hybrid and vitamin D-responsive element-based luciferase assays were used to measure the vitamin D receptor pathway activation as a marker for metabolite uptake. Regression analysis demonstrated significantly lower serum 25(OH)D concentration for clinical trial participants with 1F_2, 1S_2, or 2_2 isotypes (P < 0.01) compared with 1S_1S. Consistent with these in vivo observations, cellular data revealed that 25(OH)D uptake varied less by GC isotype only at the higher concentration tested (P = 0.05), while 1,25(OH)2D uptake differed markedly by GC isotype across concentration and assay (P < 0.01). The 1F_1S and 1F_2 isotypes produced the greatest reporter gene induction with 1,25(OH)2D treatment and, while activation varied less with 25(OH)D, the 2_2 isotype demonstrated increased induction at the lower concentration. These results suggest that vitamin D metabolite concentration and delivery to colon cells may vary not only by GC isotype, but also that certain isotypes may more effectively deliver 1,25(OH)2D versus 25(OH)D. Overall, these results may help identify populations at risk for cancer and potential recipients of targeted chemoprevention.
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20 MeSH Terms
Role of α-crystallin B as a regulatory switch in modulating cardiomyocyte apoptosis by mitochondria or endoplasmic reticulum during cardiac hypertrophy and myocardial infarction.
Mitra A, Basak T, Datta K, Naskar S, Sengupta S, Sarkar S
(2013) Cell Death Dis 4: e582
MeSH Terms: Animals, Apoptosis, Cardiomegaly, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Gene Expression Regulation, Heat-Shock Proteins, Male, Mitochondria, Myocardial Infarction, Myocytes, Cardiac, RNA, Small Interfering, Rats, Rats, Wistar, Signal Transduction, Taurochenodeoxycholic Acid, Voltage-Dependent Anion Channel 1
Show Abstract · Added November 3, 2017
Cardiac hypertrophy and myocardial infarction (MI) are two major causes of heart failure with different etiologies. However, the molecular mechanisms associated with these two diseases are not yet fully understood. So, this study was designed to decipher the process of cardiomyocyte apoptosis during cardiac hypertrophy and MI in vivo. Our study revealed that mitochondrial outer membrane channel protein voltage-dependent anion channel-1 (VDAC1) was upregulated exclusively during cardiac hypertrophy, whereas 78 kDa glucose-regulated protein (GRP78) was exclusively upregulated during MI, which is an important upstream regulator of the endoplasmic reticulum (ER) stress pathway. Further downstream analysis revealed that mitochondrial pathway of apoptosis is instrumental in case of hypertrophy, whereas ER stress-induced apoptosis is predominant during MI, which was confirmed by treatment with either siRNA against VDAC1 or ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Very interestingly, our data also showed that the expression and interaction of small heat-shock protein α-crystallin B (CRYAB) with VDAC1 was much more pronounced during MI compared with either hypertrophy or control. The study demonstrated for the first time that two different organelles--mitochondria and ER have predominant roles in mediating cardiomyocyte death signaling during hypertrophy and MI, respectively, and activation of CRYAB acts as a molecular switch in bypassing mitochondrial pathway of apoptosis during MI.
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17 MeSH Terms
Cytochrome P450 107U1 is required for sporulation and antibiotic production in Streptomyces coelicolor.
Tian Z, Cheng Q, Yoshimoto FK, Lei L, Lamb DC, Guengerich FP
(2013) Arch Biochem Biophys 530: 101-7
MeSH Terms: Anti-Bacterial Agents, Bacterial Proteins, Cytochrome P-450 Enzyme System, Glycochenodeoxycholic Acid, Mutation, Oxidation-Reduction, Streptomyces coelicolor
Show Abstract · Added March 7, 2014
The filamentous bacterium Streptomyces coelicolor has a complex life cycle involving the formation of hair-like aerial mycelia on the colony surface, which differentiate into chains of spores. Genes required for the initiation of aerial mycelium formation have been termed 'bld' (bald), describing the smooth, undifferentiated colonies of mutant strains. We report the identification of a new bld gene designated as sco3099 and biochemical analysis of its encoded enzyme, cytochrome P450 (P450, or CYP) 107U1. Deletion of sco3099 resulted in a mutant defective in aerial hyphae sporulation and sensitive to heat shock, indicating that P450 107U1 plays a key role in growth and development of S. coelicolor. This is the first P450 reported to participate in a sporulation process in Streptomycetes. The substrate and catalytic properties of P450 107U1 were further investigated in mass spectrometry-based metabolomic studies. Glycocholic acid (from the medium) was identified as a substrate of P450 107U1 and was oxidized to glyco-7-oxo-deoxycholic acid. Although this reaction is apparently not relevant to the observed sporulation deficiency, it suggests that P450 107U1 might exert its physiological function by oxidizing other steroid-like molecules.
Copyright © 2013 Elsevier Inc. All rights reserved.
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7 MeSH Terms
Campylobacter jejuni type VI secretion system: roles in adaptation to deoxycholic acid, host cell adherence, invasion, and in vivo colonization.
Lertpiriyapong K, Gamazon ER, Feng Y, Park DS, Pang J, Botka G, Graffam ME, Ge Z, Fox JG
(2012) PLoS One 7: e42842
MeSH Terms: Agar, Animals, Bacterial Proteins, Bacterial Secretion Systems, Campylobacter Infections, Campylobacter jejuni, Cell Adhesion, Cell Proliferation, Deoxycholic Acid, Genes, Bacterial, Genetic Complementation Test, Hemolysin Proteins, Interleukin-10, Mice, Mice, Transgenic, Multigene Family, Mutation, Phenotype
Show Abstract · Added April 13, 2017
The recently identified type VI secretion system (T6SS) of proteobacteria has been shown to promote pathogenicity, competitive advantage over competing microorganisms, and adaptation to environmental perturbation. By detailed phenotypic characterization of loss-of-function mutants, in silico, in vitro and in vivo analyses, we provide evidence that the enteric pathogen, Campylobacter jejuni, possesses a functional T6SS and that the secretion system exerts pleiotropic effects on two crucial processes--survival in a bile salt, deoxycholic acid (DCA), and host cell adherence and invasion. The expression of T6SS during initial exposure to the upper range of physiological levels of DCA (0.075%-0.2%) was detrimental to C. jejuni proliferation, whereas down-regulation or inactivation of T6SS enabled C. jejuni to resist this effect. The C. jejuni multidrug efflux transporter gene, cmeA, was significantly up-regulated during the initial exposure to DCA in the wild type C. jejuni relative to the T6SS-deficient strains, suggesting that inhibition of proliferation is the consequence of T6SS-mediated DCA influx. A sequential modulation of the efflux transporter activity and the T6SS represents, in part, an adaptive mechanism for C. jejuni to overcome this inhibitory effect, thereby ensuring its survival. C. jejuni T6SS plays important roles in host cell adhesion and invasion as T6SS inactivation resulted in a reduction of adherence to and invasion of in vitro cell lines, while over-expression of a hemolysin co-regulated protein, which encodes a secreted T6SS component, greatly enhanced these processes. When inoculated into B6.129P2-IL-10(tm1Cgn) mice, the T6SS-deficient C. jejuni strains did not effectively establish persistent colonization, indicating that T6SS contributes to colonization in vivo. Taken together, our data demonstrate the importance of bacterial T6SS in host cell adhesion, invasion, colonization and, for the first time to our knowledge, adaptation to DCA, providing new insights into the role of T6SS in C. jejuni pathogenesis.
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18 MeSH Terms
Polymorphic variation in the GC and CASR genes and associations with vitamin D metabolite concentration and metachronous colorectal neoplasia.
Hibler EA, Hu C, Jurutka PW, Martinez ME, Jacobs ET
(2012) Cancer Epidemiol Biomarkers Prev 21: 368-75
MeSH Terms: Aged, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Dietary Fiber, Double-Blind Method, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Male, Middle Aged, Neoplasms, Second Primary, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Receptors, Calcium-Sensing, Risk Factors, Treatment Outcome, Ursodeoxycholic Acid, Vitamin D, Vitamin D-Binding Protein
Show Abstract · Added December 29, 2014
BACKGROUND - Vitamin D levels and calcium intake have been associated with risk of colorectal neoplasia, and genetic variation in vitamin D pathway genes may affect circulating vitamin D metabolite concentrations and/or risk for colorectal lesions. This study evaluated associations between polymorphic variation in the Gc-globulin (GC) and calcium-sensing receptor (CASR) and odds for metachronous colorectal neoplasia and vitamin D metabolite concentrations.
METHODS - Participants from the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) trials (n = 1,439) were analyzed using a single-nucleotide polymorphism (SNP) tagging approach, with a subset (n = 404) of UDCA trial participants for whom vitamin D metabolite concentrations were also available. A total of 25 GC and 35 CASR tagSNPs were evaluated using multiple statistical methods.
RESULTS - Principal components analyses did not reveal gene-level associations between GC or CASR and colorectal neoplasia; however, a significant gene-level association between GC and 25(OH)D concentrations (P < 0.01) was observed. At the individual SNP level and following multiple comparisons adjustments, significant associations were observed between seven GC (rs7041, rs222035, rs842999, rs1155563, rs12512631, rs16846876, and rs1746825) polymorphisms and circulating measures of 25(OH)D (adjusted P < 0.01) and CASR SNP rs1042636 and proximal colorectal neoplasia (adjusted P = 0.01).
CONCLUSIONS - These results show a possible association between variation in CASR and odds of colorectal neoplasia as well as the potential role of variation in GC with circulating 25(OH)D concentrations.
IMPACT - Additional research is warranted to determine the mechanism of GC genotype in influencing 25(OH)D concentrations and to further elucidate the role of CASR in colorectal neoplasia.
©2011 AACR.
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21 MeSH Terms
PLC-gamma1 regulates fibronectin assembly and cell aggregation.
Crooke CE, Pozzi A, Carpenter GF
(2009) Exp Cell Res 315: 2207-14
MeSH Terms: Animals, Cell Aggregation, Cells, Cultured, Culture Media, Conditioned, Deoxycholic Acid, Fibroblasts, Fibronectins, Integrin alpha5beta1, Mice, Mice, Knockout, Phospholipase C gamma
Show Abstract · Added February 24, 2014
Phospholipase C-gamma1 (PLC-gamma1) mediates cell adhesion and migration through an undefined mechanism. Here, we examine the role of PLC-gamma1 in cell-matrix adhesion in a hanging drop assay of cell aggregation. Plcg1 Null (-/-) mouse embryonic fibroblasts formed aggregates that were larger and significantly more resistant to dissociation than cells in which PLC-gamma1 is re-expressed (Null+ cells). Aggregate formation could be disrupted by inhibition of fibronectin interaction with integrins, indicating that fibronectin assembly may mediate aggregate formation. Fibronectin assembly was mediated by integrin alpha5beta1 in both cell lines, while assays measuring fibronectin assembly revealed increased assembly in the Null cells. Null and Null+ cells exhibited equivalent fibronectin mRNA levels and equivalent levels of fibronectin protein in pulse-labeling experiments. However, levels of secreted fibronectin in the conditioned medium were increased in Null cells. The data implicates a negative regulatory role for PLC-gamma1 in cell aggregation by controlling the secretion of fibronectin into the media and its assembly into fibrils.
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11 MeSH Terms
Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells.
Merchant NB, Rogers CM, Trivedi B, Morrow J, Coffey RJ
(2005) Surgery 138: 415-21
MeSH Terms: Amphiregulin, Bile Acids and Salts, Cell Line, Tumor, Cell Membrane, Cell Polarity, Cholic Acid, Colonic Neoplasms, Deoxycholic Acid, EGF Family of Proteins, ErbB Receptors, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Ligands, Radioimmunoassay
Show Abstract · Added August 12, 2010
BACKGROUND - Secondary bile acids such as deoxycholic acid (DCA) are known to promote colorectal cancer (CRC). Increasing evidence suggests that DCA-induced signaling is mediated by activation of the epidermal growth factor receptor (EGFR). We have shown that activation of the EGFR induces up-regulation of cyclooxygenase 2, basolateral release of prostaglandins (PGs), and mitogenesis in a polarizing human colon cancer cell line, HCA-7. The purpose of this study was to determine the mechanism by which DCA activates EGFR in human polarizing CRC cell lines HCA-7 and HCT-8.
METHODS - A primary, non-tumor-promoting bile acid (cholic acid [CA]) and a secondary, tumor-promoting bile acid, DCA, were added to the apical and basolateral compartment of polarized HCA-7 and HCT-8 cells. These cells were pretreated with monoclonal antibody 528, a monoclonal antibody that inhibits ligand binding to EGFR, or with WAY-022, a selective inhibitor of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease-17 (TACE/ADAM-17), which cleaves amphiregulin (AR) to its mature, soluble form from the basolateral cell membrane. AR levels were measured in the apical and basolateral medium and cell lysates by radioimmunoassay. PGs were measured in the apical and basolateral medium by gas chromatography/mass spectrometry.
RESULTS - Basolateral delivery of DCA, but not CA, preferentially stimulated release of AR into the basolateral medium compared with cell lysates of polarized HCA-7 and HCT-8 cells. Basolateral delivery of DCA resulted in increased basolateral PGE2 levels (P < .05), and this effect was attenuated by pretreatment with monoclonal antibody 528 (P < .05). Inhibiting cell surface cleavage of AR with WAY-022 before DCA treatment reduced AR (P < .05) and PGE2 (P < .05) levels in the basolateral medium.
CONCLUSION - DCA, but not CA, results in compartment-specific, ligand-dependent activation of EGFR and subsequent increased basolateral PGE2 levels. The mechanism of DCA-induced EGFR activation is ligand-dependent and is controlled, at least in part, at the level of AR release from the basolateral cell membrane.
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15 MeSH Terms