Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice

Fu, Zidong Donna; Cui, Julia Yue; Klaassen, Curtis D.

doi:10.1194/jlr.m053124

Cited by 51 publications

(64 citation statements)

References 56 publications

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“…Cholic acid (CA) and chenodeoxycholic acid (CDCA) (and muricholic acids in mice), are primary BAs. Some secondary BAs include deoxycholic acid (DCA), LCA, and ursodeoxycholic acid (UDCA) (32). …”

Section: Gut Bacterial Metabolites Co-metabolites and Other MImentioning

confidence: 99%

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Remote Sensing Between Liver and Intestine: Importance of Microbial Metabolites

Cui

2017

Curr Pharmacol Rep

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Recent technological advancements including metagenomics sequencing and metabolomics have allowed the discovery of critical functions of gut microbiota in obesity, malnutrition, neurological disorders, asthma, and xenobiotic metabolism. Classification of the human gut microbiome into distinct “enterotypes” has been proposed to serve as a new paradigm for understanding the interplay between microbial variation and human disease phenotypes, as many organs are affected by gut microbiota modifications during the pathogenesis of diseases. Gut microbiota remotely interacts with liver and other metabolic organs of the host through various microbial metabolites that are absorbed into the systemic circulation. Purpose of review The present review summarizes recent literature regarding the importance of gut microbiota in modulating the physiological and pathological responses of various host organs, and describes the functions of the known microbial metabolites that are involved in this remote sensing process, with a primary focus on the gut microbiota-liver axis. Recent findings Under physiological conditions, gut microbiota modulates the hepatic transcriptome, proteome, and metabolome, most notably down-regulating cytochrome P450 3a mediated xenobiotic metabolism. Gut microbiome also modulates the rhythmicity in liver gene expression, likely through microbial metabolites, such as butyrate and propionate that serve as epigenetic modifiers. Additionally, the production of host hormones such as primary bile acids and glucagon like peptide 1 is altered by gut microbiota to modify intermediary metabolism of the host. Summary Dysregulation of gut microbiota is implicated in various liver diseases such as alcoholic liver disease, non-alcoholic steatohepatitis, liver cirrhosis, cholangitis, and liver cancer. Gut microbiota modifiers such as probiotics and prebiotics are increasingly recognized as novel therapeutic modalities for liver and other types of human diseases.

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Section: Gut Bacterial Metabolites Co-metabolites and Other MImentioning

confidence: 99%

“…We have several publication demonstrating that BA homeostasis can be affected by various factors, such as age (30, 33), gender (30), diet (34, 35), and drugs (32). Disruption of the enterohepatic circulation of BAs can give rise to cholestasis and NAFLD, which may progress to fibrosis and cirrhosis.…”

Section: Gut Bacterial Metabolites Co-metabolites and Other MImentioning

confidence: 99%

Remote Sensing Between Liver and Intestine: Importance of Microbial Metabolites

Cui

2017

Curr Pharmacol Rep

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“…Hydrophobic BAs are potent inflammatory chemical that cause injury to liver (Chiang 2013). In vitro and in vivo studies indicate that statins can alter BA metabolism in hepatocytes (Byun et al 2014;Fu et al 2014). The rate-limiting enzyme for the classic pathway of BA synthesis in the liver is Cyp7a1 (Chiang 2013).…”

Section: Manuscript To Be Reviewedmentioning

confidence: 99%

Peer Review #1 of "Atorvastatin alters the expression of genes related to bile acid metabolism and circadian clock in livers of mice (v0.1)"

2017

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Atorvastatin is a HMG-CoA reductase inhibitor used for hyperlipidemia. Atorvastatin is generally safe but may induce cholestasis. The present study aimed to examine the effects of atorvastatin on hepatic gene expression related to bile acid metabolism and homeostasis, as well as the expression of circadian clock genes in livers of mice. Methods: Adult male mice were given atorvastatin (10, 30, and 100 mg/kg, po) daily for 30 days, and blood biochemistry, histopathology, and gene expression were examined. Results: Repeated administration of atorvastatin did not affect animal body weight gain or liver weights. Serum enzyme activities were in the normal range. Histologically, the high dose of atorvastatin produced scattered swollen hepatocytes, foci of feathery-like degeneration, together with increased expression of Egr-1 and metallothionein-1. Atorvastatin increased the expression of Cyp7a1 in the liver, along with FXR and SHP. In contract, atorvastatin decreased the expression of bile acid transporters Ntcp, Bsep, Ostα, and Ostβ. The most dramatic change was the 30-fold induction of Cyp7a1. Because Cyp7a1 is a circadian clock-controlled gene, we further examined the effect of atorvastatin on clock gene expression. Atorvastatin increased the expression of clock core master genes Bmal1 and Npas2, decreased the expression of clock feedback genes Per2, Per3, and the clock targeted genes Dbp and Tef, whereas it had no effect on Cry1 and Nr1d1 expression. Conclusion: Repeated administration of atorvastatin affects bile acid metabolism and markedly increases the expression of the bile acid synthesis rate-limiting enzyme gene Cyp7a1, together with alterations in the expression of circadian clock genes.

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“…Grapeseed proanthocyanidin has also been found to enhance the excretion of bile acid by up-regulating CYP7A1 but lowering the expression of LXRα in hamsters (Jiao et al, 2010). Some previous studies demonstrated that other receptors, such as farnesoid X receptor (FXR) and PPARγ, or microRNAs may also regulate CYP7A1 and ABCA1 transcription and be responsible for the cholesterol homeostasis (Davalos & Fernandez-Hernando, 2013;Fu, Cui, & Klaassen, 2014;Tu, Moss-Pierce, Ford, & Jiang, 2013).…”

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confidence: 94%