ArticleJournal of hepatology2015
Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis.
Article in Journal of hepatology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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33 citing papers in PubMed, 64 citations in OpenAlex.
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- Downregulation of hepatic sulfotransferase 1E1 expression associated with decreased expression of multidrug resistance-associated protein 2.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Specific Hepatorenal Toxicity and Cross-Species Susceptibility of Eight Representative Pesticides.Toxics · 2025Article
- The Role of the Intestinal Microbiome in the Pathogenesis and Treatment of Hyperuricemia: A Review.Food science & nutrition · 2025Review
- The Effect of Radixin on the Function and Expression of Organic Anion Transporting Polypeptide 1B1.Biology · 2025Article
- Drug-Induced Liver Injury Associated With Emerging Cancer Therapies.Liver international : official journal of the International Association for the Study of the Liver · 2025Review
- Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis.Cell death & disease · 2024Article
- Oligomerization of drug transporters: Forms, functions, and mechanisms.Acta pharmaceutica Sinica. B · 2024Review
- Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review.Journal of clinical and translational hepatology · 2024Review
- Chishao (Frontiers in pharmacology · 2024Article
- Melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response.Molecular and cellular biochemistry · 2023Article
- Contribution of radixin and ezrin to the maintenance of hepatocytes' excretory function in health and disease.Heliyon · 2023Article
- A modular analysis of bile canalicular function and its implications for cholestasis.American journal of physiology. Gastrointestinal and liver physiology · 2023Review
- Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis.Cell death discovery · 2023Article
- Hepatic Aquaporin 10 Expression Is Downregulated by Activated NFκB Signaling in Human Obstructive Cholestasis.Gastro hep advances · 2023Article
- FXR Signaling-Mediated Bile Acid Metabolism Is Critical for Alleviation of Cholesterol Gallstones byMicrobiology spectrum · 2022Article
- Article
- A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis.EMBO molecular medicine · 2021Article
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Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsMultidrug resistance-associated protein 2 (MRP2) excretes conjugated organic anions including bilirubin and bile acids. Malfunction of MRP2 leads to jaundice in patients. Studies in rodents indicate that Radixin plays a critical role in determining Mrp2 canalicular membrane expression. However, it is not known how human hepatic MRP2 expression is regulated in cholestasis.
methodsWe assessed liver MRP2 expression in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, and investigated the regulatory mechanism in HepG2 cells.
resultsWestern blot detected that liver MRP2 protein expression in obstructive cholestatic patients (n=30) was significantly reduced to 25% of the non-cholestatic controls (n=23). Immunoprecipitation identified Ezrin but not Radixin associating with MRP2 in human livers, and the increased amount of phospho-Ezrin Thr567 was positively correlated with the amount of co-precipitated MRP2 in cholestatic livers, whereas Ezrin and Radixin total protein levels were unchanged in cholestasis. Further detailed studies indicate that Ezrin Thr567 phosphorylation plays an important role in MRP2 internalization in HepG2 cells. Since increased expression of PKCα, δ and ε were detected in these cholestatic livers, we further confirmed that these PKCs stimulated Ezrin phosphorylation and reduced MRP2 membrane expression in HepG2 cells. Finally, we identified GP78 as the key ubiquitin ligase E3 involved in MRP2 proteasome degradation.
conclusionsActivation of liver PKCs during cholestasis leads to Ezrin Thr567 phosphorylation resulting in MRP2 internalization and degradation where ubiquitin ligase E3 GP78 is involved. This process provides a mechanistic explanation for jaundice seen in patients with obstructive cholestasis.
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