Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice

Tang, Weiqing; Ma, Yinyan; Yu, Liqing

doi:10.1002/hep.21380

Cited by 23 publications

(23 citation statements)

References 49 publications

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“…This fi nding is consistent with previous reports that pitavastatin increased the mRNA of Abca1 in rat hepatoma cell lines ( 31 ) and simvastatin promoted Abca1 expression in mice with atherogenesis ( 47 ). A synergistic hypocholesterolemic effect could be potentially achieved by simultaneously inhibiting cholesterol biosynthesis and promoting Abcg5/Abcg8-mediated cholesterol excretion ( 48 ). Therefore, enhanced cholesterol excretion is likely an additional mechanism for atorvastatin to lower cholesterol.…”

Section: Discussionsupporting

confidence: 92%

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

Cui

Klaassen

2014

Journal of Lipid Research

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This article is available online at http://www.jlr.orgStatins are a class of drugs that are used to lower cholesterol levels by specifi cally inhibiting HMG-CoA reductase, which is the rate-limiting enzyme in cholesterol biosynthesis in the liver. Statins reduce LDL (bad cholesterol) as much as 20-60%, lower triglycerides, and slightly increase HDL (good cholesterol) ( 1, 2 ). Therefore, statins are used as the most effective drugs for treating CVDs. Commercially available statins include atorvastatin (Lipitor), fl uvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). Atorvastatin, the best-selling statin, is very potent in lowering LDL levels in patients with CVD ( 3 ).The most important statin uptake transporters in the liver are the organic anion transporting polypeptides (OATP/SLCO1B1 and 1B3 in humans, Oatp/Slco1b2 in mice) ( 4-6 ). The Na + /taurocholate cotransporting polypeptide (NTCP/SLC10A1) also plays a role in statin uptake into hepatocytes ( 5, 7 ). Moreover, several effl ux transporters are important for transporting statins out of hepatocytes, such as the multidrug resistance-associated protein 2 (Mrp2/Abcc2) ( 8 ), breast cancer resistant protein (Bcrp/ Abstract Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profi ling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12 ␣ -OH/non12 ␣ -OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7 ␣ -hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na + /taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the effl ux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fi broblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol effl ux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine. Supplementary key words ultra-performance liquid chromatographytandem mass spectrometry • cholesterol 7 ␣ -hydroxylase • farnesoid X receptor signaling

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Section: Discussionsupporting

confidence: 92%

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

Cui

Klaassen

2014

Journal of Lipid Research

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“…In animal models, hepatic expression of ABCG5/8 has been shown to be increased following statin therapy, which was associated with an increase in biliary cholesterol concentration ( 51,52 ). Lally et al ( 53 ) reported a signifi cant increase in intestinal ABGC5/8 mRNA expression in diabetic patients following treatment with statins.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

Tremblay

Lamarche

Lemelin

et al. 2011

Journal of Lipid Research

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The relationship between elevated plasma levels of LDLcholesterol (LDL-C) and the risk of atherosclerosis has been very well established ( 1-3 ). Clinical trials have shown that reduction of LDL-C constitutes a primary strategy for the prevention and regression of coronary heart disease ( 4 ). Plasma cholesterol levels are regulated by feedback mechanisms including exogenous cholesterol absorption through the gastrointestinal tract and endogenous cholesterol synthesis by various tissues. Several studies have shown that the amount of dietary cholesterol absorbed also infl uences endogenous cholesterol synthesis ( 5-7 ). The newly identifi ed Niemann-Pick C1-like 1 (NPC1L1) protein expressed at the apical membrane of enterocytes has been shown to play a crucial role in the absorption of cholesterol and plant sterol ( 8 ). Several physiological determinants and pharmacological agents modulate cholesterol homeostasis, including genetic factors, body weight, ezetimibe therapy, and 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR) inhibitors (statins) therapy, the rate-limiting step in the cholesterol biosynthesis pathway ( 9 ). For instance, obese subjects show an increase in cholesterol synthesis with an associated decrease in cholesterol absorption ( 10, 11 ). Ezetimibe therapy has been shown to reduce intestinal cholesterol absorption while reciprocally elevating synthesis ( 12 ). These fi ndings suggest the presence of a reciprocal relationship between cholesterol absorption and synthesis, as a change in one vector results in a compensatory and opposing change in the other. Although recent data suggest that statin therapy is associated

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“…The qPCR was performed as described previously ( 39 ). All primers used for qPCR have been published previously ( 39,40 ).…”

Section: Quantitative Real-time Pcr (Qpcr)mentioning

confidence: 99%

Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

Lin

Liu

et al. 2010

Journal of Lipid Research

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Plasma cholesterol is hyperresponsive to statin in ABCG5/ABCG8 transgenic mice

Cited by 23 publications

References 49 publications

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

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

Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

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