OATP1B3-1B7, a novel organic anion transporting polypeptide, is modulated by FXR ligands and transports bile acids

Organic anion transporting polypeptide (OATP) 1B3-1B7 (LST-3TM12) is a member of the OATP1B [solute carrier organic anion transporter ( ) ] family. This transporter is not only functional but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3-1...

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Vydané v:American journal of physiology: Gastrointestinal and liver physiology Ročník 317; číslo 6; s. G751
Hlavní autori: Malagnino, Vanessa, Hussner, Janine, Issa, Ali, Midzic, Angela, Meyer Zu Schwabedissen, Henriette E
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.12.2019
Predmet:
Antineoplastic Agents - pharmacology
Bile Acids and Salts - physiology
Biological Transport - physiology
Gene Expression Regulation
Gene Regulatory Networks - physiology
HeLa Cells
Hep G2 Cells
Humans
Isoxazoles - pharmacology
Organic Anion Transporters - genetics
Organic Anion Transporters - metabolism
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors
Receptors, Cytoplasmic and Nuclear - genetics
Solute Carrier Organic Anion Transporter Family Member 1B3 - genetics
Solute Carrier Organic Anion Transporter Family Member 1B3 - metabolism
Solute Carrier Proteins - genetics
Solute Carrier Proteins - metabolism
Transcription Factors
Transcriptional Activation
LST-3TM12
SLCO1B7
farnesoid X receptor
OATP1B3-1B7
SLCO1B3
ISSN:1522-1547, 1522-1547
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Shrnutí:Organic anion transporting polypeptide (OATP) 1B3-1B7 (LST-3TM12) is a member of the OATP1B [solute carrier organic anion transporter ( ) ] family. This transporter is not only functional but also expressed in the membrane of the smooth endoplasmic reticulum of hepatocytes and enterocytes. OATP1B3-1B7 is a splice variant of in which the initial part is encoded by , whereas the rest of the mRNA originates from the gene locus of . In this study, we not only showed that and the mRNA encoding for OATP1B3-1B7 share the 5' untranslated region but also that silencing of an initial exon lowered the amount of and of mRNA in Huh-7 cells. To validate the assumption that both transcripts are regulated by the same promoter we tested the influence of the bile acid sensor farnesoid X receptor (FXR) on their transcription. Treatment of Huh-7 and HepaRG cells with activators of this known regulator of OATP1B3 not only increased but also OATP1B3-1B7 mRNA transcription. Applying a heterologous expression system, we showed that several bile acids interact with OATP1B3-1B7 and that taurocholic acid and lithocholic acid are OATP1B3-1B7 substrates. As OATP1B3-1B7 is located in the smooth endoplasmic reticulum, it may grant access to metabolizing enzymes. In accordance are our findings showing that the OATP1B3-1B7 inhibitor bromsulphthalein significantly reduced uptake of bile acids into human liver microsomes. Taken together, we report that OATP1B3-1B7 transcription can be modulated with FXR agonists and antagonists and that OATP1B3-1B7 transports bile acids. Our study on the transcriptional regulation of the novel organic anion transporting polypeptide (OATP) 1B3-1B7 concludes that the promoter of solute carrier organic anion transporter ( ) governs transcription. Moreover, the transcription of OATP1B3-1B7 can be modulated by farnesoid X receptor (FXR) agonists and antagonists. FXR is a major regulator in bile acid homeostasis that links OATP1B3-1B7 to this physiological function. Findings in transport studies with OATP1B3-1B7 suggest that this transporter interacts with the herein tested bile acids.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1522-1547
1522-1547
DOI:10.1152/ajpgi.00330.2018