Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis

Pan, Qiong; Zhang, Xiaoxun; Zhang, Liangjun; Cheng, Ying; Zhao, Nan; Li, Fengju; Zhou, Xueqian; Chen, Sheng; Li, Jianwei; Xu, Senlin; Huang, Dingde; Chen, Yue; Li, Lihua; Wang, Huaizhi; Chen, Wensheng; Cai, Shi‐Ying; Boyer, James L.; Chai, Jin

doi:10.1053/j.gastro.2018.07.031

Cited by 37 publications

(71 citation statements)

References 27 publications

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“…SLCO4A1 is expressed throughout the body at the plasma membrane [535]. Substrates of this transporter include prostaglandins, benzylpenicillin, taurocholate, and thyroxine [537]. SLCO4A1 is a prognostic marker for colorectal cancer, with higher expression indicating a poorer prognosis [538].…”

Section: Slcomentioning

confidence: 99%

A guide to plasma membrane solute carrier proteins

2020

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This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.

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Section: Slcomentioning

confidence: 99%

A guide to plasma membrane solute carrier proteins

2020

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“…To induce hepatic fibrosis, mice were injected intraperitoneally with 0.75 ml/kg of CCl 4 twice a week for 8 wk, with olive oil as a control. BDL was performed under isoflurane anesthesia as previously described by Pan et al (14). All animal experiments were performed following a guideline from the Animal Experiment Administration Committee of the Nanjing Medical University.…”

Section: Animals and Bone Marrow Transplantationmentioning

confidence: 99%

RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1–TLR4–NF‐κB pathway in macrophages

et al. 2019

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Liver fibrosis is an important pathologic process in injured liver tissues. A protein kinase, receptor‐interacting protein (RIP)3, plays a crucial role in mediating different diseases. However, the role of RIP3 in macrophages in liver fibrosis has not yet been studied. In our study, we found that RIP3 expression was up‐regulated in liver tissues and macrophages of humans and mice with liver fibrosis. Absence of RIP3 in macrophages could alleviate inflammation and macrophage or neutrophil accumulation in mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. Importantly, RIP3 deficiency in macrophages could decrease CCl4‐induced and BDL‐induced liver fibrosis in mice. Moreover, RIP3 deficiency could inhibit the TLR4–NF‐κB pathway through suppressing Rho‐associated coiled‐coil containing protein kinase (ROCK)l in macrophages. To explore the connection of ROCK1 and RIP3 in macrophages of mice with liver fibrosis in vivo, ROCK1‐overexpressed macrophages were infused to RIP3‐deficient mice, which resulted in increased inflammation and liver fibrosis. In conclusion, our findings suggest that RIP3 plays a crucial proinflammatory role in liver fibrosis by regulating the ROCK1–TLR4–NF‐κB signaling pathway in macrophages and therefore may be a potential therapeutic target for immune‐mediated liver fibrosis.—Wei, S., Zhou, H., Wang, Q., Zhou, S., Li, C, Liu, R., Qiu, J., Shi, C, Lu, L. RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1‐TLR4‐NF‐κB pathway in macrophages. FASEB J. 33, 11180–11193 (2019). http://www.fasebj.org

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“…Because MRP4 showed a partial role in the basolateral export in BSEP R1090X i-Heps, we explored the possible contribution of other transporters that are capable of carrying bile acids. Among the SLC family, OST⍺/ SLC51A , OSTβ/ SLC51B , OATP3A1/ SLCO3A1 , and OATP1B3/ SLCO1B3 are known to export conjugated bile acid from the basolateral domain ( Alrefai and Gill, 2007 ; Ballatori et al., 2009 ; Briz et al., 2006 ; Bruyn et al., 2011 ; Pan et al., 2018 ). We found gene upregulation of OSTβ/ SLC51B and OATP3A1/ SLCO3A1 in BSEP R1090X i-Heps and downregulation of OST⍺/ SLC51A ( Figure 4 E).…”

Section: Resultsmentioning

confidence: 99%

Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation

et al. 2021

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Summary The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency.

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Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis

Abstract: We found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

Cited by 37 publications

References 27 publications

A guide to plasma membrane solute carrier proteins

A guide to plasma membrane solute carrier proteins

RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1–TLR4–NF‐κB pathway in macrophages

Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation

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