Dataset Information

Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans.

ABSTRACT:

Background & aims

OATP1B3/SLCO1B3 is a human liver-specific transporter for the clearance of endogenous compounds (eg, bile acid [BA]) and xenobiotics. The functional role of OATP1B3 in humans has not been characterized, as SLCO1B3 is poorly conserved among species without mouse orthologs.

Methods

Slc10a1-knockout (Slc10a1^-/-), Slc10a1^hSLCO1B3 (endogenous mouse Slc10a1 promoter-driven human-SLCO1B3 expression in Slc10a1^-/- mice), and human SLCO1B3 liver-specific transgenic (hSLCO1B3-LTG) mice were generated and challenged with 0.1% ursodeoxycholic-acid (UDCA), 1% cholic-acid (CA) diet, or bile duct ligation (BDL) for functional studies. Primary hepatocytes and hepatoma-PLC/RPF/5 cells were used for mechanistic studies.

Results

Serum BA levels in Slc10a1^-/- mice were substantially increased with or without 0.1% UDCA feeding compared with wild-type (WT) mice. This increase was attenuated in Slc10a1^hSLCO1B3-mice, indicating that OATP1B3 functions as a significant hepatic BA uptake transporter. In vitro assay using primary hepatocytes from WT, Slc10a1^-/-, and Slc10a1^hSLCO1B3-mice indicated that OATP1B3 has a similar capacity in taking up taurocholate/TCA as Ntcp. Furthermore, TCA-induced bile flow was significantly impaired in Slc10a1^-/- mice but partially recovered in Slc10a1^hSLC01B3-mice, indicating that OATP1B3 can partially compensate the NTCP function in vivo. Liver-specific overexpression of OATP1B3 markedly increased the level of hepatic conjugated BA and cholestatic liver injury in 1% CA-fed and BDL mice. Mechanistic studies revealed that conjugated BAs stimulated Ccl2 and Cxcl2 in hepatocytes to increase hepatic neutrophil infiltration and proinflammatory cytokine production (eg, IL-6), which activated STAT3 to repress OATP1B3 expression by binding to its promoter.

Conclusions

Human OATP1B3 is a significant BA uptake transporter and can partially compensate Ntcp for conjugated BA uptake in mice. Its downregulation in cholestasis is an adaptive protective response.

SUBMITTER: Pan Q

PROVIDER: S-EPMC10394288 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans.

Pan Qiong Q Zhu Guanyu G Xu Ziqian Z Zhu Jinfei J Ouyang Jiafeng J Tong Yao Y Zhao Nan N Zhang Xiaoxun X Cheng Ying Y Zhang Liangjun L Tan Ya Y Li Jianwei J Zhang Chengcheng C Chen Wensheng W Cai Shi-Ying SY Boyer James L JL Chai Jin J

Cellular and molecular gastroenterology and hepatology 20230503 2

<h4>Background & aims</h4>OATP1B3/SLCO1B3 is a human liver-specific transporter for the clearance of endogenous compounds (eg, bile acid [BA]) and xenobiotics. The functional role of OATP1B3 in humans has not been characterized, as SLCO1B3 is poorly conserved among species without mouse orthologs.<h4>Methods</h4>Slc10a1-knockout (Slc10a1<sup>-/-</sup>), Slc10a1<sup>hSLCO1B3</sup> (endogenous mouse Slc10a1 promoter-driven human-SLCO1B3 expression in Slc10a1<sup>-/-</sup> mice), and human SLCO1B3 ...[more]

PMID: 37146714

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Dataset Information

Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans.

Background & aims

Methods

Results

Conclusions

Publications

Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans.

Similar Datasets

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