Dynamic Localization of Hepatocellular Transporters: Role in Biliary Excretion and Impairment in Cholestasis
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Published:2019-05-14
Issue:7
Volume:26
Page:1113-1154
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ISSN:0929-8673
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Container-title:Current Medicinal Chemistry
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language:en
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Short-container-title:CMC
Author:
Roma Marcelo G.1, Barosso Ismael R.1, Miszczuk Gisel S.1, Crocenzi Fernando A.1, Pozzi Enrique J. Sánchez1
Affiliation:
1. Instituto de Fisiologia Experimental (IFISE) - Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), S2002LRL, Rosario, Argentina
Abstract
Bile flow generation is driven by the vectorial transfer of osmotically active compounds from sinusoidal blood into a confined space, the bile canaliculus. Hence, localization of hepatocellular transporters relevant to bile formation is crucial for bile secretion. Hepatocellular transporters are localized either in the plasma membrane or in recycling endosomes, from where they can be relocated to the plasma membrane on demand, or endocytosed when the demand decreases. The balance between endocytic internalization/ exocytic targeting to/from this recycling compartment is therefore the main determinant of the hepatic capability to generate bile, and to dispose endo- and xenobiotics. Furthermore, the exacerbated endocytic internalization is a common pathomechanisms in both experimental and human cholestasis; this results in bile secretory failure and, eventually, posttranslational transporter downregulation by increased degradation. This review summarizes the proposed structural mechanisms accounting for this pathological condition (e.g., alteration of function, localization or expression of F-actin or F-actin/transporter cross-linking proteins, and switch to membrane microdomains where they can be readily endocytosed), and the mediators implicated (e.g., triggering of “cholestatic” signaling transduction pathways). Lastly, we discussed the efficacy to counteract the cholestatic failure induced by transporter internalization of a number of therapeutic experimental approaches based upon the use of compounds that trigger exocytic targetting of canalicular transporters (e.g., cAMP, tauroursodeoxycholate). This therapeutics may complement treatments aimed to transcriptionally improve transporter expression, by affording proper localization and membrane stability to the de novo synthesized transporters.
Funder
Agencia Nacional de Promoción Científica y Tecnológica Consejo Nacional de Investigaciones Científicas y Técnicas
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology,Molecular Medicine,Drug Discovery,Biochemistry,Organic Chemistry
Reference332 articles.
1. Esteller A. World J Gastroenterol, Physiology of bile secretion.,, 2008, 14,, 5641-5649, 2. Crocenzi FA, Mottino AD, Roma MG. Curr Med Chem, Regulation of synthesis and trafficking of canalicular transporters and its alteration in acquired hepatocellular cholestasis: Experimental therapeutic strategies for its prevention.,, 2004, 11,, 501-524, 3. Jonker JW, Stedman CAM, Liddle C, Downes M. Front Biosci (Landmark Ed), Hepatobiliary ABC transporters: physiology, regulation and implications for disease.,, 2009, 14,, 4904-4920, 4. Staudinger JL, Woody S, Sun M, Cui W. Drug Metab Rev, Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver.,, 2013, 45,, 48-59, 5. Dolganiuc A. World J Gastroenterol, Role of lipid rafts in liver health and disease.,, 2011, 17,, 2520-2535,
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