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Peter W. Swaan - One of the best experts on this subject based on the ideXlab platform.

  • resveratrol promotes degradation of the human bile acid transporter asbt SLC10A2
    Biochemical Journal, 2014
    Co-Authors: Paresh P Chothe, Peter W. Swaan
    Abstract:

    The sodium/bile acid co-transporter ASBT [apical sodium-dependent bile acid transporter; SLC10A2 (solute carrier family 10 member 2)] plays a key role in the enterohepatic recycling of the bile acids and indirectly contributes to cholesterol homoeostasis. ASBT inhibitors reportedly lower plasma triglyceride levels and increase HDL (high-density lipoprotein) cholesterol levels. RSV (resveratrol), a major constituent of red wine, is known to lower LDL (low-density lipoprotein) cholesterol levels, but its mechanism of action is still unclear. In the present study, we investigated the possible involvement of ASBT in RSV-mediated cholesterol-lowering effects. We demonstrate that RSV inhibits ASBT protein expression and function via a SIRT1 (sirtuin 1)-independent mechanism. The effect was specific to ASBT since other transporters involved in cholesterol homoeostasis, NTCP (SLC10A1), OSTα (SLC51A) and ABCG1 (ATP-binding cassette G1), remained unaffected. ASBT inhibition by RSV was reversed by proteasome inhibitors (MG-132 and lactacystin) and the ubiquitin inhibitor LDN57444, suggesting involvement of the ubiquitin–proteasome pathway. Immunoprecipitation revealed high levels of ubiquitinated ASBT after RSV treatment. Phosphorylation at Ser 335 and Thr 339 was shown previously to play a role in proteosomal degradation of rat ASBT. However, mutation at corresponding residues in rat ASBT revealed that phosphorylation does not contribute to RSV-mediated degradation of ASBT. Combined, our data indicate that RSV promotes ASBT degradation via the ubiquitin–proteasome pathway without requiring phosphorylation. We conclude that regulation of ASBT expression by RSV may have clinical relevance with regard to the observed cholesterol-lowering effects of RSV.

  • Transmembrane domain II of the human bile acid transporter SLC10A2 coordinates sodium translocation.
    The Journal of biological chemistry, 2013
    Co-Authors: Hairat Sabit, Sairam S. Mallajosyula, Alexander D. Mackerell, Peter W. Swaan
    Abstract:

    Human apical sodium-dependent bile acid transporter (hASBT, SLC10A2) is responsible for intestinal reabsorption of bile acids and plays a key role in cholesterol homeostasis. We used a targeted and systematic approach to delineate the role of highly conserved transmembrane helix 2 on the expression and function of hASBT. Cysteine mutation significantly depressed transport activity for >60% of mutants without affecting cell surface localization of the transporter. All mutants were inaccessible toward chemical modification by membrane-impermeant MTSET reagent, strongly suggesting that transmembrane 2 (TM2) plays an indirect role in bile acid substrate translocation. Both bile acid uptake and sodium dependence of TM2 mutants revealed a distinct α-helical periodicity. Kinetic studies with conservative and non-conservative mutants of sodium sensitive residues further underscored the importance of Gln(75), Phe(76), Met(79), Gly(83), Leu(86), Phe(90), and Asp(91) in hASBT function. Computational analysis indicated that Asp(91) may coordinate with sodium during the transport cycle. Combined, our data propose that a consortium of sodium-sensitive residues along with previously reported residues (Thr(134), Leu(138), and Thr(149)) from TM3 may form the sodium binding and translocation pathway. Notably, residues Gln(75), Met(79), Thr(82), and Leu(86) from TM2 are highly conserved in TM3 of a putative remote bacterial homologue (ASBTNM), suggesting a universal mechanism for the SLC10A transporter family.

  • the solute carrier family 10 slc10 beyond bile acid transport
    Molecular Aspects of Medicine, 2013
    Co-Authors: Tatiana Claro Da Silva, James E Polli, Peter W. Swaan
    Abstract:

    The solute carrier (SLC) family 10 (SLC10) comprises influx transporters of bile acids, steroidal hormones, various drugs, and several other substrates. Because the seminal transporters of this family, namely, sodium/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2), were primarily bile acid transporters, the term "sodium bile salt cotransporting family" was used for the SLC10 family. However, this notion became obsolete with the finding of other SLC10 members that do not transport bile acids. For example, the sodium-dependent organic anion transporter (SOAT; SLC10A6) transports primarily sulfated steroids. Moreover, NTCP was shown to also transport steroids and xenobiotics, including HMG-CoA inhibitors (statins). The SLC10 family contains four additional members, namely, P3 (SLC10A3; SLC10A3), P4 (SLC10A4; SLC10A4), P5 (SLC10A5; SLC10A5) and SLC10A7 (SLC10A7), several of which were unknown or considered hypothetical until approximately a decade ago. While their substrate specificity remains undetermined, great progress has been made towards their characterization in recent years. Explicitly, SLC10A4 may participate in vesicular storage or exocytosis of neurotransmitters or mastocyte mediators, whereas SLC10A5 and SLC10A7 may be involved in solute transport and SLC10A3 may have a role as a housekeeping protein. Finally, the newly found role of bile acids in glucose and energy homeostasis, via the TGR5 receptor, sheds new light on the clinical relevance of ASBT and NTCP. The present mini-review provides a brief summary of recent progress on members of the SLC10 family.

Coen C. Paulusma - One of the best experts on this subject based on the ideXlab platform.

  • the lipid flippase heterodimer atp8b1 cdc50a is essential for surface expression of the apical sodium dependent bile acid transporter SLC10A2 asbt in intestinal caco 2 cells
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Vincent A Van Der Mark, Kam S Homok, Rudi D De Waart, Heleen W Voogt, Ronald Oude P J Elferink, Merit M Tabbers, A S Knisely, Coen C. Paulusma
    Abstract:

    Abstract Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.

  • The lipid flippase heterodimer ATP8B1–CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Vincent A Van Der Mark, Heleen W Voogt, Dirk R. De Waart, Merit M Tabbers, A S Knisely, Coen C. Paulusma
    Abstract:

    Abstract Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1–CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption.

Paul A Dawson - One of the best experts on this subject based on the ideXlab platform.

  • Analysis of the Ileal Bile Acid Transporter Gene, SLC10A2, in Subjects With Familial Hypertriglyceridemia
    2016
    Co-Authors: Martha W. Love, John D. Brunzell, Bo Angelin, William C. Duane, Ann L. Craddock, Paul A Dawson
    Abstract:

    Abstract—Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na/bile acid cotransporter gene (SLC10A2) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5 flanking sequence of SLC10A2. The SLC10A2 missense mutations and 5 flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2. The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2. (Arterioscler Thromb Vasc Biol. 2001;21:2039-2045.) Key Words: bile acids hypertriglyceridemia genetics complex disease Familial hypertriglyceridemia (FHTG) is a heritable dis-order of lipid metabolism characterized by elevate

  • SLC10A2 null mice uncover colon cancer promoting actions of endogenous fecal bile acids
    Carcinogenesis, 2015
    Co-Authors: Jeanpierre Raufman, Paul A Dawson, James E Polli, Anuradha Rao, Cinthia B Drachenberg, Jonathon Heath, Aaron C Shang, Min Zhan, Kunrong Cheng
    Abstract:

    Although epidemiological evidence in humans and bile acid feeding studies in rodents implicate bile acids as tumor promoters, the role of endogenous bile acids in colon carcinogenesis remains unclear. In this study, we exploited mice deficient in the ileal apical sodium-dependent bile acid transporter (ASBT, encoded by SLC10A2) in whom fecal bile acid excretion is augmented more than 10-fold. Wild-type and Asbt-deficient (SLC10A2 (-/-) ) male mice were treated with azoxymethane (AOM) alone to examine the development of aberrant crypt foci, the earliest histological marker of colon neoplasia and a combination of AOM and dextran sulfate sodium to induce colon tumor formation. Asbt-deficient mice exhibited a 54% increase in aberrant crypt foci, and 70 and 59% increases in colon tumor number and size, respectively. Compared to littermate controls, Asbt-deficient mice had a striking, 2-fold increase in the number of colon adenocarcinomas. Consistent with previous studies demonstrating a role for muscarinic and epidermal growth factor receptor signaling in bile acid-induced colon neoplasia, increasing bile acid malabsorption was associated with M3 muscarinic and epidermal growth factor receptor expression, and activation of extracellular signal-related kinase, a key post-receptor signaling molecule.

  • functional characterization of genetic variants in the apical sodium dependent bile acid transporter asbt SLC10A2
    Journal of Gastroenterology and Hepatology, 2011
    Co-Authors: Brenda F Leake, Paul A Dawson, Brad L Urquhart, Jamie Gregor, Richard B Kim
    Abstract:

    Background and Aims The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity.

  • the sodium bile salt cotransport family slc10
    Pflügers Archiv: European Journal of Physiology, 2004
    Co-Authors: Bruno Hagenbuch, Paul A Dawson
    Abstract:

    The SLC10 family of sodium/bile salt cotransporters contains over 50 members in animal, plant and bacterial species. In man, two well-characterized members and three orphan transporters are known. The Na+/taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile salt transporter (ASBT; SLC10A2) are critical components of the enterohepatic circulation of bile salts. NTCP and ASBT are cotransporters that mediate sodium-dependent, electrogenic uptake of mainly bile salts into hepatocytes (NTCP), biliary epithelial cells, ileal enterocytes and renal proximal tubular cells (ASBT).

  • localization of the ileal sodium bile acid cotransporter gene SLC10A2 to human chromosome 13q33
    Genomics, 1996
    Co-Authors: Melissa H Wong, P N Rao, Mark J Pettenati, Paul A Dawson
    Abstract:

    This report describes the localization of the human ileal sodium-bile acid cotransporter gene (SLC10A2) to human chromosome 13q33 using fluorescence in situ hybridization. The article discusses some possible roles for this gene in inherited disorders of bile acid and cholesterol metabolism. 9 refs., 1 fig.

Ryuhei Kanamoto - One of the best experts on this subject based on the ideXlab platform.

  • importance of uncharged polar residues and proline in the proximal two thirds pro107 ser128 of the highly conserved region of mouse ileal na dependent bile acid transporter SLC10A2 in transport activity and cellular expression
    BMC Physiology, 2013
    Co-Authors: Tohru Saeki, Ryuhei Kanamoto, Kosuke Sato, Shiho Ito, Keisuke Ikeda
    Abstract:

    SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act not only as detergents but also as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. SLC10A family members and the homologous genes of various species share a highly conserved region corresponding to Gly104–Pro142 of SLC10A2. The functional importance of this region has not been fully elucidated. To elucidate the functional importance of this region, we previously performed mutational analysis of the uncharged polar residues and proline in the distal one-third (Thr130–Pro142) of the highly conserved region in mouse SLC10A2. In this study, proline and uncharged polar residues in the remaining two-thirds of this region in mouse SLC10A2 were subjected to mutational analysis, and taurocholic acid uptake and cell surface localization were examined. Cell surface localization of SLC10A2 is necessary for bile acid absorption. Mutants in which Asp or Leu were substituted for Pro107 (P107N or P107L) were abundantly expressed, but their cell surface localization was impaired. The S126A mutant was completely impaired in cellular expression. The T110A and S128A mutants exhibited remarkably enhanced membrane expression. The S112A mutant was properly expressed at the cell surface but transport activity was completely lost. Replacement of Tyr117 with various amino acids resulted in reduced transport activity. The degree of reduction roughly depended on the van der Waals volume of the side chains. The functional importance of proline and uncharged polar residues in the highly conserved region of mouse SLC10A2 was determined. This information will contribute to the design of bile acid-conjugated prodrugs for efficient drug delivery or SLC10A2 inhibitors for hypercholesterolemia treatment.

  • mutational analysis of uncharged polar residues and proline in the distal one third thr130 pro142 of the highly conserved region of mouse SLC10A2
    Bioscience Biotechnology and Biochemistry, 2009
    Co-Authors: Tohru Saeki, Satoko Mizushima, Kazumitsu Ueda, Kimikazu Iwami, Ryuhei Kanamoto
    Abstract:

    Solute carrier family member 2 (SLC10A2) reabsorbs bile acids at the distal terminus of the ileum in an Na+-dependent manner. Alignment of deduced amino acid sequences of SLC10 family members and homologous genes in various species revealed a highly conserved region that corresponds to Gly104–Pro142 of SLC10A2. To elucidate the functional importance of this region, uncharged polar residues and Pro in the distal one-third of this region in mouse SLC10A2 (mSLC10A2) were submitted to mutational analysis, and taurocholic acid uptake and cell surface localization were evaluated. In addition to mutations that abolished almost all of the transport activity with and without cellular localization failure (P142V and T130A respectively), a mutation that perhaps affected affinity for taurocholic acid was identified (T134A). These results suggest that the highly conserved region contains residues involved in the substrate interaction, function, and cellular localization of mSLC10A2.

Eduard F. Stange - One of the best experts on this subject based on the ideXlab platform.

  • effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels meta analysis of three independent cohorts
    BMC Medical Genetics, 2011
    Co-Authors: Anke Tonjes, Olga Renner, Simone Harsch, Eduard F. Stange, Henning Wittenburg, Frank Lammert, Jan Halbritter, Michael Stumvoll, Peter Kovacs
    Abstract:

    Background Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans.

  • a variant of the SLC10A2 gene encoding the apical sodium dependent bile acid transporter is a risk factor for gallstone disease
    PLOS ONE, 2009
    Co-Authors: Olga Renner, Simone Harsch, Elke Schaeffeler, Matthias Schwab, Stefan Winter, Marcin Krawczyk, Jonas Rosendahl, Henning Wittenburg, Frank Lammert, Eduard F. Stange
    Abstract:

    Background: Cholelithiasis is a multifactorial process and several mechanisms of gallstone formation have been postulated. As one of these mechanisms, a decreased expression of the ileal apical sodium-dependent bile acid transporter gene SLC10A2 in gallstone carriers was described previously. In this study the SLC10A2 gene was investigated to identify novel genetic variants and their association with gallstone formation. Methodology/Principal Findings: Study subjects were selected with the presence or absence of gallstones confirmed by ultrasound and medical history. Genomic DNA was obtained from blood leukocytes. Sequence analysis was performed of all six exonic and flanking regions as well as of 2,400 base pairs of the SLC10A2 promoter in a cohort of gallstone carriers and control subjects from Stuttgart, Germany. Genotype frequencies of newly identified genetic variants (n=6) and known single nucleotide polymorphisms (n=24) were established using MALDI-TOF mass spectrometry. Six new genetic variants were found within the SLC10A2 gene. Although none of the variants was linked to gallstone disease in the Stuttgart cohort overall, the minor allele of SNP rs9514089 was more prevalent in male non-obese gallstone carriers (p=0.06680, OR=11.00). In a separate population from Aachen, Germany, the occurrence of rs9514089 was two-fold higher in gallstone patients (22%) than in corresponding controls (11%) (p=0.00995, OR=2.19). In the pooled Aachen/Stuttgart cohort rs9514089 was highly significantly linked to cholelithiasis (p=0.00767, OR=2.04). A more frequent occurrence was observed for male gallstone carriers (22%) compared to controls (9%) (p=0.01017, OR=2.99), for the total normal weight group (p=0.00754, OR=2.90), and for male non-obese gallstone patients (p=0.01410, OR=6.85). Moreover, for the minor allele of rs9514089 an association with low plasma cholesterol levels was found especially in gallstone carriers (p=0.05). Conclusions/Significance: We have identified SLC10A2 as a novel susceptibility gene for cholelithiasis in humans. Comprehensive statistical analysis provides strong evidence that rs9514089 is a genetic determinant especially in male nonobese gallstone carriers. The minor allele of rs9514089 is related to differences in plasma cholesterol levels among the subjects.

  • Mutation screening of apical sodium-dependent bile acid transporter (SLC10A2): novel haplotype block including six newly identified variants linked to reduced expression
    Human Genetics, 2009
    Co-Authors: Olga Renner, Simone Harsch, Elke Schaeffeler, Matthias Schwab, Dietmar M. Klass, Wolfgang Kratzer, Eduard F. Stange
    Abstract:

    The apical sodium-dependent bile acid transporter ( SLC10A2 ) plays a key role in the reabsorption of luminal bile acids into the enterohepatic circulation. Rare variations in SLC10A2 have been reported to be associated with Crohn’s disease, primary bile acid malabsorption and familial hypertriglyceridemia; however, variants associated with reduced SLC10A2 expression have not been reported to date. In this study, we have performed a sequence analysis of SLC10A2 using genomic DNA of 93 individuals. A new haplotype structure was identified including ten variants with complete linkage disequilibrium (LD′ = 1.0, r ^2 = 1.0) of which six polymorphisms were novel. The sequence variants were confirmed in three independent cohorts ( n  = 1,290) by a recently established MALDI-TOF MS iPLEX™ assay. Remarkably, haplotype carriers with the minor allele exhibited significant reduced ileal SLC10A2 expression on mRNA levels (2.6-fold, P  = 0.0009) and protein levels (2.4-fold, P  = 0.0157). In future studies a single tag SNP selected of this haplotype block will provide reliable genetic testing to investigate systemically the influence of the SLC10A2 haplotype for disease susceptibility and/or drug response.