Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis.
BACKGROUND
Cholesterol cholelithiasis (gallstone disease) is a common disease in the Western world. The aim of the present study was to analyze the hepatic expression of a number of nuclear receptors involved in bile acid metabolism in human cholesterol gallstone disease.


METHODS
Surgical liver biopsies were obtained from 11 patients with untreated cholesterol cholelithiasis and nine gallstone-free subjects; mRNA levels of cholesterol 7alpha-hydroxylase (CYP7A1) and related nuclear receptors and coactivators were assayed by quantitative real-time RT-PCR.


RESULTS
No differences between the two groups were detected in mRNA levels of CYP7A1 and related nuclear receptors, with the exception of peroxysome proliferator-activated receptor-gamma coactivator 1 (PGC-1), which was significantly (P < 0.01) less expressed in gallstone subjects. Expression of PGC-1 was linearly correlated with farnesoid X receptor (FXR) in gallstone patients (r = 0.87 on a log scale, P < 0.01), but not in control subjects; in gallstone patients PGC-1 expression was also correlated with hepatocyte nuclear factor 4 (HNF-4) (r = 0.78, P < 0.01).


CONCLUSIONS
These findings suggest that PGC-1 can play a role in the prevention of cholesterol gallstone disease in humans; this might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models and other coactivators. The present data might help to understand the pathophysiology and possibly focus on new therapeutical targets in cholesterol gallstone disease.
Bertolotti
M
M
Dipartimento di Medicine e Specialità Mediche, Divisione di Medicina 3, University of Modena and Reggio Emilia, 41100 Modena, Italy. bertolotti.marco@unimore.it
Gabbi
C
C
Anzivino
C
C
Mitro
N
N
Godio
C
C
De Fabiani
E
E
Crestani
M
M
Del Puppo
M
M
Ricchi
M
M
Carulli
L
L
Rossi
A
A
Loria
P
P
Carulli
N
N
D001647:Bile Acids and Salts / Q000096:biosynthesis; D015415:Biomarkers / Q000097:blood; D002769:Cholelithiasis / Q000378:metabolism*; D002783:Cholestenones / Q000097:blood; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000032:analysis / Q000235:genetics; D006801:Humans; D008099:Liver / Q000737:chemistry*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D015415:Biomarkers; D002783:Cholestenones; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C496592:HNF4A protein, human; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C002656:7 alpha-hydroxy-4-cholesten-3-one