Pravastatiini on vesiliukoinen, päinvastoin kuin muut statiinit.
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.
CONCLUSION: Our data suggested that pravastatin prevents cholesterol gallstone diseases via the increase of FXR, LXRalpha and CYP7A1 in human hepatocytes.
- PMID:
- 24463082
- [PubMed - indexed for MEDLINE]
Toinen lähde:
J Gastroenterol Hepatol. 2011 Oct;26(10):1544-51. doi: 10.1111/j.1440-1746.2011.06748.x.
- Pravastatin modulates liver bile acid and cholesterol homeostasis in rats with chronic cholestasis. Kolouchova G1, Brcakova E, et al.
BACKGROUND AND AIM: The administration of pravastatin to patients with cholestatic liver disease has suggested the potential of the drug with regard to reducing raised plasma cholesterol and bile acid levels. Information about the mechanisms associated with this effect is lacking. Thus, the aim of the present study is to evaluate pravastatin effects on the liver bile acid and cholesterol homeostasis in healthy and cholestatic rats.
METHODS: Control sham-operated and reversibly bile duct-obstructed (BDO) rats were treated with pravastatin (1 or 5 mg/kg) or the vehicle alone for 7 days after surgery.
RESULTS: Lower doses of pravastatin reduced bile acid plasma concentrations in cholestatic animals. The effect was associated with reduced liver mRNA expression of Cyp7a1, Cyp8b1, Mrp2, Ugt1a1 and the increased expression of Bsep (Abcb11)
In addition, BDO-induced increase in the liver content of cholesterol was normalized by pravastatin. The change was accompanied by the reduced liver expression of Hmg-CoA reductase, LDL receptor, and Acat2, and induced the expression of Abca1 and Mdr2. These changes corresponded with the upregulation of nuclear receptors LXRα and PPARα, and the downregulation of FXR, CAR, SREBP-2 (sterol regulatory element.binding protein ) and HNF1α (Hepatic Nuclear Factor).
High doses of pravastatin lacked any positive effects on bile acids and cholesterol homeostasis, and blocked bile formation through the reduction of the biliary excretion of bile acids.
CONCLUSIONS: Pravastatin rendered a positive reduction in BDO-induced increases in plasma bile acid concentrations and cholesterol liver content, mainly through the transcriptionally-mediated downregulation of genes involved in the synthesis of these compounds in the liver.
© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.Comment in
- Effects of statins on cholestasis: good, bad or indifferent? [J Gastroenterol Hepatol. 2011]
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