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Ezetimibe Inhibits Expression of Acid Sphingomyelinase in Liver and Intestine

  • Original Article
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Lipids

Abstract

Ezetimibe inhibits cholesterol absorption in the intestine. Sphingomyelin has strong interactions with cholesterol. We investigated the effects of ezetimibe on Sphingomyelinase (SMase) expression in intestine and liver. After feeding rats with ezetimibe (5 mg/kg per day) for 14 days, acid SMase activities in the liver and in the proximal part of small intestine were reduced by 34 and 25%, respectively. Alkaline SMase (alk-SMase) was increased in the proximal part of the small intestine. Administration of lower doses of ezetimibe reduced acid SMase only in the liver by 14% (P < 0.05). In cell culture studies, ezetimibe decreased acid SMase activity in Hep G2 and Caco-2 cells dose-dependently. The reductions were more rapid for Hep G2 cells than for Caco-2 cells. Western blot showed that acid SMase protein was decreased in both Hep G2 and Caco-2 cells by 100 μM ezetimibe. The SM content was increased in Hep G2 cells but not Caco-2 cells, and total cholesterol content was increased in both cell lines 24 h after stimulation with 100 μM ezetimibe. Mevastatin, the inhibitor of cholesterol synthesis, induced a mild increase in acid SMase activity in Hep G2 cells but not Caco-2 cells. Following the reduction of acid SMase, ezetimibe at high dose slightly increased alk-SMase activity. In conclusion, the study demonstrates an inhibitory effect of ezetimibe on acid SMase activity and expression in both liver and intestine.

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Abbreviations

Alk-SMase:

Alkaline sphingomyelinase

NPC1:

Niemann–Pick C1

NPC1L1:

Niemann–Pick C1 like 1 protein

SM:

Sphingomyelin

SMase:

Sphingomyelinase

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Acknowledgments

The work was supported by grants from Albert Påhlsson Foundation, Swedish Cancer Foundation, Swedish Research Council, and the Research Foundation of Lund University Hospital. Merck Sharp & Dohme (Sweden) AB is thanked for providing ezetimibe and financial support for this study.

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Authors and Affiliations

  1. Gastroenterology and Nutrition Lab, BMC, B11, Institution of Clinical Sciences, Lund University, 221 84, Lund, Sweden

    Yajun Cheng, Fuli Liu, Jun Wu, Yao Zhang, Åke Nilsson & Rui-Dong Duan

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  1. Yajun Cheng
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  2. Fuli Liu
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  3. Jun Wu
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  4. Yao Zhang
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  5. Åke Nilsson
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  6. Rui-Dong Duan
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Correspondence to Rui-Dong Duan.

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Cheng, Y., Liu, F., Wu, J. et al. Ezetimibe Inhibits Expression of Acid Sphingomyelinase in Liver and Intestine. Lipids 44, 897–906 (2009). https://doi.org/10.1007/s11745-009-3343-1

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  • DOI: https://doi.org/10.1007/s11745-009-3343-1

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