Ae2-Deficient Mice Develop Antimitochondrial Antibodies and Other Features Resembling Primary Biliary Cirrhosis

Salas, January T.; Bañales, Jesús M.; Sarvide, Sarai; Recalde, Sergio; Ferrer, Alejandro; Uriarte, Iker; Elferink, Ronald P.J. Oude; Prieto, Jesús; Medina, Juan F.

doi:10.1053/j.gastro.2008.02.020

Cited by 182 publications

(154 citation statements)

References 30 publications

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“…Since siRNAmediated suppression of Ae2 in rat cholangiocytes decreased secretin-and taurocholate-stimulated apical HCO 3 -secretion (Banales et al, 2006), decreased Ae2-mediated bile secretion secondary to inflammatory and cytokine-mediated damage may contribute to primary biliary cirrhosis in mouse and human (Arenas et al, 2008 (Salas et al, 2008). Ae2 expression in lymphoid cells (Alper et al, 1988) may thus be of immunological consequence.…”

Section: Disease Phenotypes Associated With Slc4a2/ae2 and Slc4a3/ae3mentioning

confidence: 99%

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Alper

2009

Journal of Experimental Biology

190

220

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SUMMARY Plasmalemmal Cl–/HCO3–exchangers are encoded by the SLC4 and SLC26 gene superfamilies, and function to regulate intracellular pH,[Cl–] and cell volume. The Cl–/HCO3– exchangers of polarized epithelial cells also contribute to transepithelial secretion and reabsorption of acid–base equivalents and Cl–. This review focuses on Na+-independent electroneutral Cl–/HCO3– exchangers of the SLC4 family. Human SLC4A1/AE1 mutations cause the familial erythroid disorders of spherocytic anemia, stomatocytic anemia and ovalocytosis. A largely discrete set of AE1 mutations causes familial distal renal tubular acidosis. The Slc4a2/Ae2–/– mouse dies before weaning with achlorhydria and osteopetrosis. A hypomorphic Ae2–/– mouse survives to exhibit male infertility with defective spermatogenesis and a syndrome resembling primary biliary cirrhosis. A human SLC4A3/AE3 polymorphism is associated with seizure disorder, and the Ae3–/– mouse has increased seizure susceptibility. The transport mechanism of mammalian SLC4/AE polypeptides is that of electroneutral Cl–/anion exchange,but trout erythroid Ae1 also mediates Cl– conductance. Erythroid Ae1 may mediate the DIDS-sensitive Cl– conductance of mammalian erythrocytes, and, with a single missense mutation, can mediate electrogenic SO42–/Cl– exchange. AE1 trafficking in polarized cells is regulated by phosphorylation and by interaction with other proteins. AE2 exhibits isoform-specific patterns of acute inhibition by acidic intracellular pH and independently by acidic extracellular pH. In contrast, AE2 is activated by hypertonicity and, in a pH-independent manner, by ammonium and by hypertonicity. A growing body of structure–function and interaction data, together with emerging information about physiological function and structure, is advancing our understanding of SLC4 anion exchangers.

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Section: Disease Phenotypes Associated With Slc4a2/ae2 and Slc4a3/ae3mentioning

confidence: 99%

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Alper

2009

Journal of Experimental Biology

190

220

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“…17 Considering these observations, we speculated that some bacterial components originating from asymptomatic or less apparent chronic bacterial infection might have function(s) in the initiation and/or development of the autoimmune status in patients with PBC, eventually leading to chronic epithelial inflammation in the liver and multiple epithelial inflammation. Recently, a strain with a dominant-negative form of TGFb receptor II, 18 IL-2 receptor a À/À mice, 19 and Ae2 a,b -deficient mice 20 have been reported as spontaneous PBC animal models. However, as these mice are genetically engineered, they might not completely reflect the onset of human PBC.…”

mentioning

confidence: 99%

Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

Haruta

Kikuchi

Hashimoto

et al. 2010

Laboratory Investigation

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“…Supporting evidence comes from the anion exchanger AE2, which is expressed on the apical membrane of cholangiocytes and secrets bicarbonate into the biliary lumen in exchange for chloride. AE2 deficient knockout mice develop features resembling primary biliary cirrhosis [32]. Human genetic variants in this gene have been shown to influence susceptibility and severity of primary biliary cirrhosis [33].…”

Section: Cholangiocytesmentioning

confidence: 99%

Bile acids in drug induced liver injury: Key players and surrogate markers

Schadt

Wolf

Philippe

et al. 2016

Clinics and Research in Hepatology and Gastroenterology

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Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.

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Ae2-Deficient Mice Develop Antimitochondrial Antibodies and Other Features Resembling Primary Biliary Cirrhosis

Cited by 182 publications

References 30 publications

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

Bile acids in drug induced liver injury: Key players and surrogate markers

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