Decreased peroxisome proliferator activated receptor alpha is associated with bile duct injury in cystic fibrosis transmembrane conductance regulator-/- mice.
BACKGROUND
Primary sclerosing cholangitis (PSC) is associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. As proof of concept that CFTR dysfunction plays a role in PSC, induction of colitis in cftr mice results in bile duct injury that can be prevented by pretreatment with docosahexaenoic acid (DHA).


OBJECTIVE
Determine whether 1) CFTR dysfunction in cftr mice through a reduction in peroxisome proliferator activated receptor (PPAR)alpha or gamma leads to bile duct injury and 2) whether DHA prevents bile duct injury through an increase in PPAR.


METHODS
Cftr and wild-type (WT) mice were treated with dextran sodium sulfate (DSS) to induce colitis with or without pretreatment with oral DHA. PPARalpha and gamma as well as tumor necrosis factor (TNF)alpha were analyzed in liver tissue. PPARalpha mice were also treated with DSS and histology examined.


RESULTS
PPARgamma mRNA levels were low, with DSS suppressing mRNA levels equally in WT and cftr mice. PPARalpha levels were no different between cftr and WT litter mates by reverse-transcription polymerase chain reaction. After DSS, WT mice showed a 9.3-fold increase in PPARalpha mRNA levels and increased nuclear localization compared with no DSS (P < 0.05), with no increase seen in cftr mice. This was not caused by changes in TNFalpha. DHA treatment led to 7.0-fold increase in PPARalpha mRNA levels in cftr mice (P < 0.01). PPARalpha mice treated with DSS did not develop bile duct injury, indicating that PPARalpha alone is not sufficient to cause bile duct inflammation.


CONCLUSIONS
DSS induced bile duct injury in cftr mice is associated with a defect in PPARalpha expression, which is reversed by DHA.
Division of Pediatric Gastroenterology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Harpreet
H
Pall
Munir M
MM
Zaman
Charlotte
C
Andersson
Steven D
SD
Freedman
D000818:Animals; D001652:Bile Ducts / Q000293:injuries / Q000473:pathology*; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000235:genetics; D016264:Dextran Sulfate / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004281:Docosahexaenoic Acids; D016264:Dextran Sulfate