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Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid–induced liver hypertrophy
Author(s) -
Xing Xiangbin,
Burgermeister Elke,
Geisler Fabian,
Einwächter Henrik,
Fan Lian,
Hiber Michaela,
Rauser Sandra,
Walch Axel,
Röcken Christoph,
Ebeling Martin,
Wright Matthew B.,
Schmid Roland M.,
Ebert Matthias P.A.
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22712
Subject(s) - farnesoid x receptor , chenodeoxycholic acid , small heterodimer partner , nuclear receptor , bile acid , biology , g protein coupled bile acid receptor , homeobox , transactivation , transcription factor , microbiology and biotechnology , medicine , endocrinology , biochemistry , gene
Farnesoid X receptor (FXR/Fxr) is a bile acid–regulated nuclear receptor that promotes hepatic bile acid metabolism, detoxification, and liver regeneration. However, the adaptive pathways under conditions of bile acid stress are not fully elucidated. We found that wild‐type but not Fxr knockout mice on diets enriched with chenodeoxycholic acid (CDCA) increase their liver/body weight ratios by 50% due to hepatocellular hypertrophy. Microarray analysis identified Hex (Hematopoietically expressed homeobox), a central transcription factor in vertebrate embryogenesis and liver development, as a novel CDCA‐ and Fxr‐regulated gene. HEX/Hex was also regulated by FXR/Fxr and CDCA in primary mouse hepatocytes and human HepG2 cells. Comparative genomic analysis identified a conserved inverted repeat‐1–like DNA sequence within a 300 base pair enhancer element of intron‐1 in the human and mouse HEX/Hex gene. A combination of chromatin immunoprecipitation, electromobility shift assay, and transcriptional reporter assays demonstrated that FXR/Fxr binds to this element and mediates HEX/Hex transcriptional activation. Conclusion : HEX/Hex is a novel bile acid–induced FXR/Fxr target gene during adaptation of hepatocytes to chronic bile acid exposure. (H EPATOLOGY 2009.)