Pravastatin activates the expression of farnesoid X receptor and liver X receptor alpha in Hep3B cells.
BACKGROUND
Statins are suggested to preserve gallbladder function by suppressing pro-inflammatory cytokines and preventing cholesterol accumulation in gallbladder epithelial cells. They also affect cross-talk among the nuclear hormone receptors that regulate cholesterol-bile acid metabolism in the nuclei of hepatocytes. However, there is controversy over whether or how statins change the expression of peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, liver X receptor alpha (LXRalpha), farnesoid X receptor (FXR), ABCG5, ABCG8, and 7alpha-hydroxylase (CYP7A1) which are directly involved in the cholesterol saturation index in bile.


METHODS
Human Hep3B cells were cultured on dishes. MTT assays were performed to determine the appropriate concentrations of reagents to be used. The protein expression of PPARalpha and PPARgamma was measured by Western blotting analysis, and the mRNA expression of LXRalpha, FXR, ABCG5, ABCG8 and CYP7A1 was estimated by RT-PCR.


RESULTS
In cultured Hep3B cells, pravastatin activated PPARalpha and PPARgamma protein expression, induced stronger expression of PPARgamma than that of PPARalpha, increased LXRalpha mRNA expression, activated ABCG5 and ABCG8 mRNA expression mediated by FXR as well as LXRalpha, enhanced FXR mRNA expression, and increased CYP7A1 mRNA expression mediated by the PPARgamma and LXRalpha pathways, together or independently.


CONCLUSIONS
Our data suggested that pravastatin prevents cholesterol gallstone diseases via the increase of FXR, LXRalpha and CYP7A1 in human hepatocytes.
Division of Gastroenterology, Department of Internal Medicine, Hallym University College of Medicine, Dongtan Sacred Heart Hospital, 40 Seokwoo-dong, Hwasung, Kyungki-Do 445-170, Republic of Korea. jinlee@medimail.co.kr.
Hyun Woo
HW
Byun
Eun Mi
EM
Hong
Soo Hee
SH
Park
Dong Hee
DH
Koh
Min Ho
MH
Choi
Hyun Joo
HJ
Jang
Sea Hyub
SH
Kae
Jin
J
Lee
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002790:Cholesterol 7-alpha-Hydroxylase; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D017035:Pravastatin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; C000605213:NR1H3 protein, human; C553219:CYP7A1 protein, human