Abstract
We determined the mechanisms of hepatobiliary injury in the lithocholic acid (LCA)-fed mouse, an increasingly used model of cholestatic liver injury. Swiss albino mice received control diet or 1% (w/w) LCA diet (for 1, 2, and 4 days), followed by assessment of liver morphology and ultrastructure, tight junctions, markers of fibrosis and key proteins of hepatobiliary function, and bile flow and composition. As expected LCA feeding led to bile infarcts, which were followed by a destructive cholangitis with activation and proliferation of periductal myofibroblasts. At the ultrastructural level, small bile ducts were frequently obstructed by crystals. Biliary-excreted fluorescence-labeled ursodeoxycholic acid accumulated in bile infarcts, whereas most infarcts did not stain with India ink injected into the common bile duct; both findings are indicative of partial biliary obstruction. Expression of the main basolateral bile acid uptake proteins (sodium-taurocholate cotransporter and organic anion-transporting polypeptide 1) was reduced, the canalicular transporters bile salt export pump and multidrug-related protein 2 were preserved, and the basolateral transporter multidrug-related protein 3 and the detoxifying enzyme sulfotransferase 2a1 were induced. Thus, we demonstrate that LCA feeding in mice leads to segmental bile duct obstruction, destructive cholangitis, periductal fibrosis, and an adaptive transporter and metabolic enzyme response.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bile Acids and Salts / metabolism
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Biliary Tract Diseases / chemically induced
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Biliary Tract Diseases / metabolism
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Biliary Tract Diseases / pathology
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Chemical and Drug Induced Liver Injury
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Cholangitis / chemically induced*
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Cholangitis / metabolism
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Cholestasis / chemically induced*
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Cholestasis / metabolism
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Cholestasis / pathology
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Detergents / toxicity*
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Diet
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Fibrosis / chemically induced
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Fibrosis / metabolism
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Fibrosis / pathology
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Fluorescence
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Lithocholic Acid / toxicity*
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Liver / drug effects*
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Liver / injuries
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Liver / metabolism
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Liver Diseases / metabolism
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Liver Diseases / pathology
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Male
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Membrane Transport Proteins / genetics
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Membrane Transport Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism
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Organic Anion Transporters / genetics
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Organic Anion Transporters / metabolism
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Organic Anion Transporters, Sodium-Dependent / genetics
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Organic Anion Transporters, Sodium-Dependent / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfotransferases / genetics
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Sulfotransferases / metabolism
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Symporters / genetics
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Symporters / metabolism
Substances
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Bile Acids and Salts
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Detergents
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Membrane Transport Proteins
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Organic Anion Transporters
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Organic Anion Transporters, Sodium-Dependent
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RNA, Messenger
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Symporters
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sodium-bile acid cotransporter
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multidrug resistance-associated protein 3
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Lithocholic Acid
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Sulfotransferases