2006/05/19 by Gernot Zollner, Hanns–Ulrich Marschall, Martin Wagner +1 · 1 citation
Chemistry · Medicine · Pharmacology, Toxicology and Pharmaceutics · #Bile Salt Export Pump #Bile acid #Biochemistry #Biology #CYP27A1 #CYP8B1 #Calcitriol receptor #Chemistry #Cholestasis #Constitutive androstane receptor #Drug Transport and Resistance Mechanisms #Drug-Induced Hepatotoxicity and Protection #Endocrinology #Enzyme #Farnesoid X receptor #G protein-coupled bile acid receptor #Internal medicine #Kidney #Liver injury #Lysosome #Medicine #Nuclear receptor #Pediatric Hepatobiliary Diseases and Treatments #Pregnane X receptor #Reabsorption #Receptor #TFEB #Transcription factor #Ursodeoxycholic acid
paper · doi:10.1021/mp060010s
openalex publication_date 2006/05/19 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Cholestasis results in intrahepatic accumulation of cytotoxic bile acids which cause liver injury ultimately leading to biliary fibrosis and cirrhosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms. Such defense mechanisms include repression of hepatic bile acid uptake and de novo bile acid synthesis. Furthermore, phase I and II bile acid detoxification is induced rendering bile acids more hydrophilic. In addition to "orthograde" export via canalicular export systems, these compounds are also excreted via basolateral "alternative" export systems into the systemic circulation followed by renal elimination. Passive glomerular filtration of hydrophilic bile acids, active renal tubular secretion, and repression of tubular bile acid reabsorption facilitate renal bile acid elimination during cholestasis. The underlying molecular mechanisms are mediated mainly at a transcriptional level via a complex network involving nuclear receptors and other transcription factors. So far, the farnesoid X receptor FXR, pregnane X receptor PXR, and vitamin D receptor VDR have been identified as nuclear receptors for bile acids. However, the intrinsic adaptive response to bile acids cannot fully prevent liver injury in cholestasis. Therefore, additional therapeutic strategies such as targeted activation of nuclear receptors are needed to enhance the hepatic defense against toxic bile acids.