Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.
Conflict of interest statement
The authors declare no conflicts of interest.
Therapeutic Targets for Cholestatic Liver InjuryBL Woolbright et al. Expert Opin Ther Targets 20 (4), 463-75. PMID 26479335. - ReviewWhile bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver inj …
Bile AcidsPMID 31643938. - ReviewBile acids are a large family of molecules that have a steroidal structure and are synthesized from cholesterol in the liver and actively secreted along with cholesterol …
Enhanced Biliary Excretion of Canalicular Membrane Enzymes in Estrogen-Induced and Obstructive Cholestasis, and Effects of Different Bile Acids in the Isolated Perfused Rat LiverL Accatino et al. J Hepatol 22 (6), 658-70. PMID 7560859.The marked increase in sodium taurocholate and taurochenodeoxycholate-mediated release of alkaline phosphatase and gamma-glutamyl transpeptidase into bile in cholestatic …
Novel Insight Into Mechanisms of Cholestatic Liver InjuryBL Woolbright et al. World J Gastroenterol 18 (36), 4985-93. PMID 23049206. - ReviewCholestasis results in a buildup of bile acids in serum and in hepatocytes. Early studies into the mechanisms of cholestatic liver injury strongly implicated bile acid-in …
Metabolic Preconditioning Protects BSEP/ABCB11 -/- Mice Against Cholestatic Liver InjuryCD Fuchs et al. J Hepatol 66 (1), 95-101. PMID 27593105.Metabolic preconditioning with subsequent changes in BA metabolism favors detoxification of potentially toxic BAs and thereby protects BSEP-/- mice from choles …
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Single-Cell Transcriptomes Reveal Characteristic Features of Mouse Hepatocytes With Liver Cholestatic InjuryN Chang et al. Cells 8 (9). PMID 31514486.Hepatocytes are the main parenchymal cells of the liver and play important roles in liver homeostasis and disease process. The heterogeneity of normal hepatocytes has bee …