1.Antibacterial drug treatment increases intestinal bile acid absorption via elevated levels of ileal apical sodium-dependent bile acid transporter but not organic solute transporter α protein.
Miyata M1, Hayashi K, Yamakawa H, Yamazoe Y, Yoshinari K. Biol Pharm Bull. 2015;38(3):493-6. doi: 10.1248/bpb.b14-00640. Epub 2014 Dec 27.
Antibacterial drug treatment increases the bile acid pool size and hepatic bile acid concentration through the elevation of hepatic bile acid synthesis. However, the involvement of intestinal bile acid absorption in the increased bile acid pool size remains unclear. To determine whether intestinal bile acid absorption contributes to the increased bile acid pool in mice treated with antibacterial drugs, we evaluated the levels of bile acid transporter proteins and the capacity of intestinal bile acid absorption. Ileal apical sodium-dependent bile acid transporter (ASBT) mRNA and protein levels were significantly increased in ampicillin (ABPC)-treated mice, whereas organic solute transporter α (OSTα) mRNA levels, but not protein levels, significantly decreased in mice. Similar alterations in the expression levels of bile acid transporters were observed in mice treated with bacitracin/neomycin/streptomycin. The capacity for intestinal bile acid absorption was evaluated by an in situ loop method.
2.Solution structure of the transmembrane 2 domain of the human melanocortin-4 receptor in sodium dodecyl sulfate (SDS) micelles and the functional implication of the D90N mutant.
Yun JH1, Kim M2, Kim K3, Lee D1, Jung Y1, Oh D1, Ko YJ4, Cho AE2, Cho HS3, Lee W5. Biochim Biophys Acta. 2015 Jun;1848(6):1294-302. doi: 10.1016/j.bbamem.2015.02.029. Epub 2015 Mar 6.
The melanocortin receptors (MCRs) are members of the G protein-coupled receptor (GPCR) 1 superfamily with seven transmembrane (TM) domains. Among them, the melanocortin-4 receptor (MC4R) subtype has been highlighted recently by genetic studies in obese humans. In particular, in a patient with severe early-onset obesity, a novel heterozygous mutation in the MC4R gene was found in an exchange of Asp to Asn in the 90th amino acid residue located in the TM 2 domain (MC4RD90N). Mutations in the MC4R gene are the most frequent monogenic causes of severe obesity and are described as heterozygous with loss of function. We determine solution structures of the TM 2 domain of MC4R (MC4RTM2) and compared secondary structure of Asp90 mutant (MC4RTM2-D90N) in a micelle environment by nuclear magnetic resonance (NMR) spectroscopy. NMR structure shows that MC4RTM2 forms a long α-helix with a kink at Gly98. Interestingly, the structure of MC4RTM2-D90N is similar to that of MC4RTM2 based on data from CD and NMR spectrum.
3.Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors.
Brighton CA1, Rievaj J1, Kuhre RE1, Glass LL1, Schoonjans K1, Holst JJ1, Gribble FM1, Reimann F1. Endocrinology. 2015 Nov;156(11):3961-70. doi: 10.1210/en.2015-1321. Epub 2015 Aug 17.
Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L-cells, we observed that taurodeoxycholate (TDCA) and taurolithocholate (TLCA) increased intracellular cAMP and Ca(2+). In primary intestinal cultures, TDCA was a more potent GLP-1 secretagogue than taurocholate (TCA) and TLCA, correlating with a stronger Ca(2+) response to TDCA. Using small-volume Ussing chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor.
4.Effect of substituent pattern and molecular weight of cellulose ethers on interactions with different bile salts.
Torcello-Gómez A1, Fernández Fraguas C, Ridout MJ, Woodward NC, Wilde PJ, Foster TJ. Food Funct. 2015 Mar;6(3):730-9. doi: 10.1039/c5fo00099h.
Some known mechanisms proposed for the reduction of blood cholesterol by dietary fibre are: binding with bile salts in the duodenum and prevention of lipid absorption, which can be partially related with the bile salt binding. In order to gain new insights into the mechanisms of the binding of dietary fibre to bile salts, the goal of this work is to study the main interactions between cellulose derivatives and two types of bile salts. Commercial cellulose ethers: methyl (MC), hydroxypropyl (HPC) and hydroxypropylmethyl cellulose (HPMC), have been chosen as dietary fibre due to their highly functional properties important in manufactured food products. Two types of bile salts: sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC), have been chosen to understand the effect of the bile salt type. Interactions in the bulk have been investigated by means of differential scanning calorimetry (DSC) and linear mechanical spectroscopy. Results show that both bile salts have inhibitory effects on the thermal structuring of cellulose ethers and this depends on the number and type of substitution in the derivatised celluloses, and is not dependent upon molecular weight.