Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy.
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.


CONCLUSIONS
HEX/Hex is a novel bile acid-induced FXR/Fxr target gene during adaptation of hepatocytes to chronic bile acid exposure.
Xing
Xiangbin
X
Department of Medicine II, Klinikum rechts der Isar, Technical University Munich, Germany.
Burgermeister
Elke
E
Geisler
Fabian
F
Einwächter
Henrik
H
Fan
Lian
L
Hiber
Michaela
M
Rauser
Sandra
S
Walch
Axel
A
Röcken
Christoph
C
Ebeling
Martin
M
Wright
Matthew B
MB
Schmid
Roland M
RM
Ebert
Matthias P A
MP
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000009:adverse effects* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006529:Hepatomegaly / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced; D007438:Introns / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C078492:HHEX protein, human; C513080:Hhex protein, mouse