Exercising the nuclear option to treat cholestasis

Karpen, Saul J.

doi:10.1002/hep.20833

Cited by 17 publications

(13 citation statements)

References 24 publications

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“…6 Based on experimental findings in cholestatic animals, we hypothesized that activation of nuclear receptors by atorvastatin may improve cholestasis via modulation of bile formation and induction of hepatic bile acid/ bilirubin metabolizing and detoxifying enzymes. 31,32 Statins have previously been shown to act, at least in part, as agonists for the nuclear pregnane X receptor. 41 Stimulation of pregnane X receptor/sterol X receptor reduces bilirubin and serum bile acid levels in humans and rodents.…”

Section: Discussionmentioning

confidence: 99%

“…[27][28][29][30] We have demonstrated previously in mice that atorvastatin stimulates the expression of genes involved in bile formation and thus ameliorates cholestasis as reflected by reduced serum bile acid levels in bile duct-ligated mice. 31,32 Additional beneficial effects of statins in cholestasis could result from a stimulation of bile acid metabolism, detoxification, and transport, which are predicted to counteract bile acid toxicity. 33 Part of these statin effects could be explained by activation of nuclear receptors such as the pregnane X receptor/sterol X receptor and peroxisome proliferator-activated receptor-␣, 31,[34][35][36] because these nuclear receptors have been shown to regulate transport and metabolism of biliary constituents.…”

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confidence: 99%

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Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

et al. 2007

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Statin therapy may target both hypercholesterolemia and cholestasis in primary biliary cirrhosis (PBC). However, little is known about the efficacy and safety of statins in PBC. The aim of this single-center study was therefore to prospectively examine the effects of atorvastatin on serum markers of cholestasis, aminotransferases, and lipid and bile acid metabolism as well as inflammatory and immunological markers in patients with PBC. Fifteen patients with early-stage PBC and an incomplete biochemical response to ursodeoxycholic acid (UDCA) therapy (defined as alkaline phosphatase 1.5-fold above the upper limit of normal after 1 year) were treated with atorvastatin 10 mg/day, 20 mg/day, and 40 mg/day for 4 weeks, respectively. Serum levels of alkaline phosphatase increased during atorvastatin 20 mg and 40 mg (P < 0.05), whereas leucine aminopeptidase and ␥-glutamyltransferase remained unchanged. No statistical differences in overall serum ALT, AST, bilirubin, and IgM levels were observed. However, atorvastatin was discontinued in 1 out of 15 patients because of ALT 2-fold above baseline, and 2 patients showed ALT elevations 3-fold above the upper limit of normal at the end of the atorvastatin treatment period. Serum total cholesterol and low-density lipoprotein cholesterol levels decreased by 35% and 49%, respectively (P < 0.001). Precursors of cholesterol biosynthesis (lanosterol, desmosterol, lathosterol) showed a similar pattern. No changes in serum bile acid levels and composition were observed during treatment. Conclusion: Atorvastatin does not improve cholestasis in PBC patients with an incomplete biochemical response to UDCA but effectively reduces serum cholesterol levels. (HEPATOLOGY 2007;46:776-784.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

et al. 2007

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“…The overlapping ability of VDR, PXR, and CAR to alter bile acid metabolism and elimination suggests that activators of these receptors may find therapeutic effect in treating cholestasis and diseases such as primary biliary cirrhosis where abnormally high levels of bile acids accumulate [153]. Indeed, the CAR activator phenobarbital and the PXR activator rifampin have shown some therapeutic benefit in the treatment of primary biliary cirrhosis [154][155][156].…”

Section: Bile Saltsmentioning

confidence: 99%

Evolution and Function of the NR1I Nuclear Hormone Receptor Subfamily (VDR, PXR, and CAR) with Respect to Metabolism of Xenobiotics and Endogenous Compounds

Reschly¹,

Krasowski²

2006

CDM

126

130

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The NR1I subfamily of nuclear hormone receptors includes the 1,25-(OH) 2 -vitamin D 3 receptor (VDR; NR1I1), pregnane X receptor (PXR; NR1I2), and constitutive androstane receptor (CAR; NR1I3). PXR and VDR are found in diverse vertebrates from fish to mammals while CAR is restricted to mammals. Current evidence suggests that the CAR gene arose from a duplication of an ancestral PXR gene, and that PXR and VDR arose from duplication of an ancestral gene, represented now by a single gene in the invertebrate Ciona intestinalis. Aside from the high-affinity effects of 1,25-(OH) 2 -vitamin D 3 on VDRs, the NR1I subfamily members are functionally united by the ability to bind potentially toxic endogenous compounds with low affinity and initiate changes in gene expression that lead to enhanced metabolism and elimination (e.g., induction of cytochrome P450 3A4 expression in humans). The detoxification role of VDR seems limited to sensing high concentrations of certain toxic bile salts, such as lithocholic acid, whereas PXR and CAR have the ability to recognize structurally diverse compounds. PXR and CAR show the highest degree of crossspecies variation in the ligand-binding domain of the entire vertebrate nuclear hormone receptor superfamily, suggesting adaptation to species-specific ligands. This review examines the insights that phylogenetic and experimental studies provide into the function of VDR, PXR, and CAR, and how the functions of these receptors have expanded to evolutionary advantage in humans and other animals.

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“…PXR is activated by a broad spectrum of lipophilic substrates (7,10,13), including xenobiotics like antibiotics, antimycotics or herbal components, and endogenous substrates such as bile acids (14) and their precursors (15). Moreover PXR is critical to the handling of bile acids (14,16,17). Bile acids in high concentrations are toxic; therefore, their metabolism and transport is tightly regulated.…”

mentioning

confidence: 99%

Pregnane X Receptor Is a Target of Farnesoid X Receptor

Jung

Mangelsdorf

Meyer

2006

Journal of Biological Chemistry

122

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The pregnane X receptor (PXR) is an essential component of the body's detoxification system. PXR is activated by a broad spectrum of xenobiotics and endobiotics, including bile acids and their precursors. Bile acids in high concentrations are toxic; therefore, their synthesis is tightly regulated by the farnesoid X receptor, and their catabolism involves several enzymes regulated by PXR. Here we demonstrate that the expression of PXR is regulated by farnesoid X receptor. Feeding mice with cholic acid or the synthetic farnesoid X receptor (FXR) agonist GW4064 resulted in a robust PXR induction. This effect was abolished in FXR knock-out mice. Long time bile acid treatment resulted in an increase of PXR target genes in wild type mice. A region containing four FXR binding sites (IR1) was identified in the mouse Pxr gene. This region was able to trigger an 8-fold induction after GW4064 treatment in transactivation studies. Deletion or mutation of single IR1 sites caused a weakened response. The importance of each individual IR1 element was assessed by cloning a triple or a single copy and was tested in transactivation studies. Two elements were able to trigger a strong response, one a moderate response, and one no response to GW4064 treatment. Mobility shift assays demonstrated that the two stronger responding elements were able to bind FXR protein. This result was confirmed by chromatin immunoprecipitation. These results strongly suggest that PXR is regulated by FXR. Bile acids activate FXR, which blocks synthesis of bile acids and also leads to the transcriptional activation of PXR, promoting breakdown of bile acids. The combination of the two mechanisms leads to an efficient protection of the liver against bile acid induced toxicity.

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Exercising the nuclear option to treat cholestasis

Cited by 17 publications

References 24 publications

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

Evolution and Function of the NR1I Nuclear Hormone Receptor Subfamily (VDR, PXR, and CAR) with Respect to Metabolism of Xenobiotics and Endogenous Compounds

Pregnane X Receptor Is a Target of Farnesoid X Receptor

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