The liver X-receptor alpha controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice

Hepatology. 2006 Aug;44(2):368-78. doi: 10.1002/hep.21259.

Abstract

Glucuronidation, an important bile acid detoxification pathway, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT1A3 is considered the major human enzyme for the hepatic C24-glucuronidation of the primary chenodeoxycholic (CDCA) and secondary lithocholic (LCA) bile acids. We identify UGT1A3 as a positively regulated target gene of the oxysterol-activated nuclear receptor liver X-receptor alpha (LXRalpha). In human hepatic cells and human UGT1A transgenic mice, LXRalpha activators induce UGT1A3 mRNA levels and the formation of CDCA-24glucuronide (24G) and LCA-24G. Furthermore, a functional LXR response element (LXRE) was identified in the UGT1A3 promoter by site-directed mutagenesis, electrophoretic mobility shift assays and chromatin immunoprecipitation experiment. In addition, LXRalpha is found to interact with the SRC-1alpha and NCoR cofactors to regulate the UGT1A3 gene, but not with PGC-1beta. In conclusion, these observations establish LXRalpha as a crucial regulator of bile acid glucuronidation in humans and suggest that accumulation of oxysterols in hepatocytes during cholestasis favors bile acid detoxification as glucuronide conjugates. LXR agonists may be useful for stimulating both bile acid detoxification and cholesterol removal in cholestatic or hypercholesterolemic patients, respectively.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism*
  • Gene Expression*
  • Glucuronosyltransferase / drug effects
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Humans
  • Hydrocarbons, Fluorinated
  • In Vitro Techniques
  • Liver X Receptors
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Orphan Nuclear Receptors
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / genetics*
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology

Substances

  • DNA-Binding Proteins
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Sulfonamides
  • TO-901317
  • UGT1A1 enzyme
  • Glucuronosyltransferase