Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid.
OBJECTIVE
Primary biliary cirrhosis (PBC) is a poorly understood disease, both in terms of its pathogenesis and the mechanism of action of its most common treatment, ursodeoxycholic acid (UDCA). We used gene expression profiling to compare liver tissue from treatment-naïve and UDCA-treated patients in order to outline some of the molecular changes associated with PBC and its treatment. PATIENTS AND EXPERIMENTAL DESIGN: Liver biopsy specimens from non-cirrhotic, treatment-naïve (n=11) patients were compared with biopsies from UDCA-treated patients (n=20) and with 10 normal, healthy female controls. Gene expression was determined using a 19K cDNA microarray. In order to determine whether the observed changes in gene expression levels were specific to PBC or generic to liver damage overall, PBC samples were also compared with chronically diseased [48 hepatitis C virus (HCV), 18 hepatitis B virus (HBV)] and acutely stressed liver tissue (25 liver biopsies taken after reperfusion of liver transplant grafts).


RESULTS
We found a gene signature specific to PBC (P<or=0.012), containing biologically plausible genes (221 genes with adjusted P</=0.05). Differences in the expression of selected genes were confirmed using real-time polymerase chain reaction. When gene expression from non-cirrhotic UDCA-treated (n=20) and UDCA-naïve liver tissue was compared, we found a striking downregulation of a number of genes involved in protein biosynthetic pathways.


CONCLUSIONS
These studies highlight the genes associated with both treatment-naïve and UDCA-treated PBC, and suggest that the effects of UDCA are mediated, at least in part, via a modulation of protein biosynthesic pathways.
Chen
Limin
L
Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada.
Borozan
Ivan
I
Milkiewicz
Piotr
P
Sun
Jing
J
Meng
Xiangbin
X
Coltescu
Catalina
C
Edwards
Aled M
AM
Ostrowski
Mario A
MA
Guindi
Maha
M
Heathcote
Elizabeth J
EJ
McGilvray
Ian D
ID
D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D006509:Hepatitis B / Q000235:genetics / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid