Organic Solute Transporter Alpha Deficiency: A Disorder With Cholestasis, Liver Fibrosis, and Congenital Diarrhea

Gao, Emily; Cheema, Huma Arshad; Waheed, Nadia K.; Mushtaq, Iqra; Erden, Nihan; Nelson‐Williams, Carol; Jain, Dhanpat; Soroka, Carol J.; Boyer, James L.; Khalil, Youssef; Clayton, Peter T.; Mistry, Pramod K.; Lifton, Richard P.; Vilarinho, Sílvia

doi:10.1002/hep.31087

Cited by 24 publications

(29 citation statements)

References 4 publications

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“…Thus, the intracellular level of bile acids in cholangiocytes may not reach levels that stress the cell as in cholestatic hepatocytes, despite both cells being exposed to millimolar levels of bile acids at their apical membranes. Several patients have been described with Ostα as well as OSTβ deficiencies that develop bile duct injury (26,27), supporting this hypothesis that OSTα-Ostβ protects the cholangiocyte from bile acid induced injury.…”

Section: Bile Acids Induce Cholangiocyte Proliferation and Inflammationmentioning

confidence: 76%

The role of bile acids in cholestatic liver injury

Cai¹,

Boyer²

2021

Ann Transl Med

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Clinical disorders that impair bile flow result in retention of bile acids and cholestatic liver injury, characterized by parenchymal cell death, bile duct proliferation, liver inflammation and fibrosis. However, the pathogenic role of bile acids in the development of cholestatic liver injury remains incompletely understood.In this review, we summarize the current understanding of this process focusing on the experimental and clinical evidence for direct effects of bile acids on each major cellular component of the liver: hepatocytes, cholangiocytes, stellate cells and immune cells. During cholestasis bile acids accumulated in the liver, causing oxidative stress and mitochondrial injury in hepatocytes. The stressed hepatocytes respond by releasing inflammatory cytokines through activation of specific signaling pathways and transcription factors. The recruited neutrophils and other immune cells then cause parenchymal cell death. In addition, bile acids also stimulate the proliferation of cholangiocytes and stellate cells that are responsible for bile duct proliferation and liver fibrosis. This review explores the evidence for bile acid involvement in these phenomena. The role of bile acid receptors, TGR5, FXR and the sphingosine-1-phosphate receptor 2 and the inflammasome are also examined. We hope that better understanding of these pathologic effects will facilitate new strategies for treating cholestatic liver injury.

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Section: Bile Acids Induce Cholangiocyte Proliferation and Inflammationmentioning

confidence: 76%

The role of bile acids in cholestatic liver injury

Cai¹,

Boyer²

2021

Ann Transl Med

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“…Only recently was a single patient with SLC51A deficiency identified. ( 6 ) A liver biopsy from this boy revealed a lobular architecture with periportal fibrosis, suggestive of early cirrhosis and minimal inflammation. His clinical presentation was more severe compared with the two cases of SLC51B deficiency, with easy bruising, two episodes of prolonged bleeding that required blood transfusions (each likely attributable to malabsorption of fat‐soluble vitamin K), and failure to thrive.…”

Section: Figmentioning

confidence: 84%

“…OSTα and OSTβ deficiency appears to have in common that patients display chronic malabsorptive diarrhea, but the number of cases are still too low to provide comprehensive disease insight. ( 6 ) OSTαβ does not exclusively transport bile salts, and its deficiency may affect transport of multiple compounds and drugs. ( 60 ) An animal model for OSTα deficiency was generated by two groups.…”

Section: Figmentioning

confidence: 99%

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

et al. 2021

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Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors, and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate most of the hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium–dependent bile acid transporter (gene SLC10A2 ) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B ). The Na + ‐taurocholate cotransporting polypeptide (gene SLC10A1 ) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11 ) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na + ‐taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium–dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion : We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.

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“…Elevations in serum gamma-glutamyltransferase and increases in bile duct proliferation and fibrosis in these cases suggest injury to cholangiocytes in the absence of OSTa-OSTb. 79 Osta KO mice do not develop this phenotype, most likely because their bile acid pool is more hydrophilic than in humans.…”

Section: Key Pointmentioning

confidence: 95%

Bile formation and secretion: An update

Boyer

Soroka

2021

Journal of Hepatology

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Bile formation is a fundamental physiological process that is vital to the survival of all vertebrates. However, little was known about the mechanisms of this secretion until after World War II. Initial studies involved classic physiologic studies in animal models and humans, which progressed to include studies in isolated cells and membrane vesicles. The advent of molecular biology then led to the identification of specific transport systems that are the determinants of this secretion. Progress in this field was reviewed in the American Physiologic Society's series on "Comprehensive Physiology" in 2013. Herein, we provide an in-depth update of progress since that time.

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Organic Solute Transporter Alpha Deficiency: A Disorder With Cholestasis, Liver Fibrosis, and Congenital Diarrhea

Cited by 24 publications

References 4 publications

The role of bile acids in cholestatic liver injury

The role of bile acids in cholestatic liver injury

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

Bile formation and secretion: An update

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