Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia

José C. Sandoval, Yumiko Nakagawa-Toyama, Daisaku Masuda, Yoshihiro Tochino, Hajime Nakaoka, Ryota Kawase, Miyako Yuasa-Kawase, Kazuhiro Nakatani, Miwako Inagaki, Kazumi Tsubakio-Yamamoto, Tohru Ohama, Akifumi Matsuyama, Makoto Nishida, Masato Ishigami, Issei Komuro, Shizuya Yamashita

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Abstract

Aim: Postprandial hypertriglyceridemia (PHTG) has been shown repeatedly to be associated with metabolic syndrome and atherosclerotic cardiovascular diseases. We have recently reported that ezetimibe inhibits PHTG in patients with type IIb hyperlipidemia. Ezetimibe was also reported to attenuate PHTG in combination with low-dose statins in patients with obesity or metabolic syndrome. We reported CD36-deficient (CD36KO) mice as a new model for PHTG, in which the synthesis of chylomicron (CM) in the small intestines is enhanced. In the current study, we investigated the effect of ezetimibe on PHTG in this mouse model of metabolic syndrome. Methods: Wild-type (WT) mice fed a western diet, and CD36KO mice fed a normal chow diet, respectively, were treated for 3 weeks with and without ezetimibe, followed by an evaluation of triglyceride (TG) concentrations by enzymatic method and by high performance liquid chromatography (HPLC) as well as those of and apolipoprotein (Apo) B-48 in plasma and intestinal lymph after oral fat loading with olive oil. Intestinal mucosa was also harvested to evaluate the transcriptional regulation of the genes involved in the intestinal production of ApoB-containing lipoproteins. Results: Ezetimibe dramatically reduced PHTG in both WT and CD36KO mice. HPLC analysis of plasma showed that the decrease in TG content in CM and CM remnants-sized particles contributed to this suppression, suggesting that CM production in the small intestines might be reduced after ezetimibe treatment. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. Both TG content and ApoB-48 mass were decreased in ezetimibe-treated mice. The quantitative RT-PCR of intestinal mucosa showed down-regulation of the mRNA expression of FATP4 and ApoB in both groups along with FABP2, DGAT1, DGAT2 and SCD1 in WT mice at postprandial state after ezetimibe treatment. Conclusion: Ezetimibe alone reduces PHTG by blocking both the absorption of cholesterol and the intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, resulting in the reduction of the formation of ApoB-48 which is necessary for the ApoB48-containing lipoprotein production in the small intestines.

Original languageEnglish
Pages (from-to)914-924
Number of pages11
JournalJournal of atherosclerosis and thrombosis
Volume17
Issue number9
DOIs
Publication statusPublished - 01-01-2010

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Hypertriglyceridemia
Apolipoprotein B-48
Chylomicrons
Small Intestine
Triglycerides
Apolipoproteins B
High performance liquid chromatography
Lymph
Intestinal Mucosa
Nutrition
Lipoproteins
Fats
Chylomicron Remnants
High Pressure Liquid Chromatography
Ezetimibe
Plasmas
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enterocytes
Hyperlipidemias
Metabolism

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine
  • Biochemistry, medical

Cite this

Sandoval, J. C., Nakagawa-Toyama, Y., Masuda, D., Tochino, Y., Nakaoka, H., Kawase, R., ... Yamashita, S. (2010). Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. Journal of atherosclerosis and thrombosis, 17(9), 914-924. https://doi.org/10.5551/jat.4929
Sandoval, José C. ; Nakagawa-Toyama, Yumiko ; Masuda, Daisaku ; Tochino, Yoshihiro ; Nakaoka, Hajime ; Kawase, Ryota ; Yuasa-Kawase, Miyako ; Nakatani, Kazuhiro ; Inagaki, Miwako ; Tsubakio-Yamamoto, Kazumi ; Ohama, Tohru ; Matsuyama, Akifumi ; Nishida, Makoto ; Ishigami, Masato ; Komuro, Issei ; Yamashita, Shizuya. / Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. In: Journal of atherosclerosis and thrombosis. 2010 ; Vol. 17, No. 9. pp. 914-924.
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abstract = "Aim: Postprandial hypertriglyceridemia (PHTG) has been shown repeatedly to be associated with metabolic syndrome and atherosclerotic cardiovascular diseases. We have recently reported that ezetimibe inhibits PHTG in patients with type IIb hyperlipidemia. Ezetimibe was also reported to attenuate PHTG in combination with low-dose statins in patients with obesity or metabolic syndrome. We reported CD36-deficient (CD36KO) mice as a new model for PHTG, in which the synthesis of chylomicron (CM) in the small intestines is enhanced. In the current study, we investigated the effect of ezetimibe on PHTG in this mouse model of metabolic syndrome. Methods: Wild-type (WT) mice fed a western diet, and CD36KO mice fed a normal chow diet, respectively, were treated for 3 weeks with and without ezetimibe, followed by an evaluation of triglyceride (TG) concentrations by enzymatic method and by high performance liquid chromatography (HPLC) as well as those of and apolipoprotein (Apo) B-48 in plasma and intestinal lymph after oral fat loading with olive oil. Intestinal mucosa was also harvested to evaluate the transcriptional regulation of the genes involved in the intestinal production of ApoB-containing lipoproteins. Results: Ezetimibe dramatically reduced PHTG in both WT and CD36KO mice. HPLC analysis of plasma showed that the decrease in TG content in CM and CM remnants-sized particles contributed to this suppression, suggesting that CM production in the small intestines might be reduced after ezetimibe treatment. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. Both TG content and ApoB-48 mass were decreased in ezetimibe-treated mice. The quantitative RT-PCR of intestinal mucosa showed down-regulation of the mRNA expression of FATP4 and ApoB in both groups along with FABP2, DGAT1, DGAT2 and SCD1 in WT mice at postprandial state after ezetimibe treatment. Conclusion: Ezetimibe alone reduces PHTG by blocking both the absorption of cholesterol and the intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, resulting in the reduction of the formation of ApoB-48 which is necessary for the ApoB48-containing lipoprotein production in the small intestines.",
author = "Sandoval, {Jos{\'e} C.} and Yumiko Nakagawa-Toyama and Daisaku Masuda and Yoshihiro Tochino and Hajime Nakaoka and Ryota Kawase and Miyako Yuasa-Kawase and Kazuhiro Nakatani and Miwako Inagaki and Kazumi Tsubakio-Yamamoto and Tohru Ohama and Akifumi Matsuyama and Makoto Nishida and Masato Ishigami and Issei Komuro and Shizuya Yamashita",
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Sandoval, JC, Nakagawa-Toyama, Y, Masuda, D, Tochino, Y, Nakaoka, H, Kawase, R, Yuasa-Kawase, M, Nakatani, K, Inagaki, M, Tsubakio-Yamamoto, K, Ohama, T, Matsuyama, A, Nishida, M, Ishigami, M, Komuro, I & Yamashita, S 2010, 'Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia', Journal of atherosclerosis and thrombosis, vol. 17, no. 9, pp. 914-924. https://doi.org/10.5551/jat.4929

Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. / Sandoval, José C.; Nakagawa-Toyama, Yumiko; Masuda, Daisaku; Tochino, Yoshihiro; Nakaoka, Hajime; Kawase, Ryota; Yuasa-Kawase, Miyako; Nakatani, Kazuhiro; Inagaki, Miwako; Tsubakio-Yamamoto, Kazumi; Ohama, Tohru; Matsuyama, Akifumi; Nishida, Makoto; Ishigami, Masato; Komuro, Issei; Yamashita, Shizuya.

In: Journal of atherosclerosis and thrombosis, Vol. 17, No. 9, 01.01.2010, p. 914-924.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia

AU - Sandoval, José C.

AU - Nakagawa-Toyama, Yumiko

AU - Masuda, Daisaku

AU - Tochino, Yoshihiro

AU - Nakaoka, Hajime

AU - Kawase, Ryota

AU - Yuasa-Kawase, Miyako

AU - Nakatani, Kazuhiro

AU - Inagaki, Miwako

AU - Tsubakio-Yamamoto, Kazumi

AU - Ohama, Tohru

AU - Matsuyama, Akifumi

AU - Nishida, Makoto

AU - Ishigami, Masato

AU - Komuro, Issei

AU - Yamashita, Shizuya

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Aim: Postprandial hypertriglyceridemia (PHTG) has been shown repeatedly to be associated with metabolic syndrome and atherosclerotic cardiovascular diseases. We have recently reported that ezetimibe inhibits PHTG in patients with type IIb hyperlipidemia. Ezetimibe was also reported to attenuate PHTG in combination with low-dose statins in patients with obesity or metabolic syndrome. We reported CD36-deficient (CD36KO) mice as a new model for PHTG, in which the synthesis of chylomicron (CM) in the small intestines is enhanced. In the current study, we investigated the effect of ezetimibe on PHTG in this mouse model of metabolic syndrome. Methods: Wild-type (WT) mice fed a western diet, and CD36KO mice fed a normal chow diet, respectively, were treated for 3 weeks with and without ezetimibe, followed by an evaluation of triglyceride (TG) concentrations by enzymatic method and by high performance liquid chromatography (HPLC) as well as those of and apolipoprotein (Apo) B-48 in plasma and intestinal lymph after oral fat loading with olive oil. Intestinal mucosa was also harvested to evaluate the transcriptional regulation of the genes involved in the intestinal production of ApoB-containing lipoproteins. Results: Ezetimibe dramatically reduced PHTG in both WT and CD36KO mice. HPLC analysis of plasma showed that the decrease in TG content in CM and CM remnants-sized particles contributed to this suppression, suggesting that CM production in the small intestines might be reduced after ezetimibe treatment. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. Both TG content and ApoB-48 mass were decreased in ezetimibe-treated mice. The quantitative RT-PCR of intestinal mucosa showed down-regulation of the mRNA expression of FATP4 and ApoB in both groups along with FABP2, DGAT1, DGAT2 and SCD1 in WT mice at postprandial state after ezetimibe treatment. Conclusion: Ezetimibe alone reduces PHTG by blocking both the absorption of cholesterol and the intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, resulting in the reduction of the formation of ApoB-48 which is necessary for the ApoB48-containing lipoprotein production in the small intestines.

AB - Aim: Postprandial hypertriglyceridemia (PHTG) has been shown repeatedly to be associated with metabolic syndrome and atherosclerotic cardiovascular diseases. We have recently reported that ezetimibe inhibits PHTG in patients with type IIb hyperlipidemia. Ezetimibe was also reported to attenuate PHTG in combination with low-dose statins in patients with obesity or metabolic syndrome. We reported CD36-deficient (CD36KO) mice as a new model for PHTG, in which the synthesis of chylomicron (CM) in the small intestines is enhanced. In the current study, we investigated the effect of ezetimibe on PHTG in this mouse model of metabolic syndrome. Methods: Wild-type (WT) mice fed a western diet, and CD36KO mice fed a normal chow diet, respectively, were treated for 3 weeks with and without ezetimibe, followed by an evaluation of triglyceride (TG) concentrations by enzymatic method and by high performance liquid chromatography (HPLC) as well as those of and apolipoprotein (Apo) B-48 in plasma and intestinal lymph after oral fat loading with olive oil. Intestinal mucosa was also harvested to evaluate the transcriptional regulation of the genes involved in the intestinal production of ApoB-containing lipoproteins. Results: Ezetimibe dramatically reduced PHTG in both WT and CD36KO mice. HPLC analysis of plasma showed that the decrease in TG content in CM and CM remnants-sized particles contributed to this suppression, suggesting that CM production in the small intestines might be reduced after ezetimibe treatment. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. Both TG content and ApoB-48 mass were decreased in ezetimibe-treated mice. The quantitative RT-PCR of intestinal mucosa showed down-regulation of the mRNA expression of FATP4 and ApoB in both groups along with FABP2, DGAT1, DGAT2 and SCD1 in WT mice at postprandial state after ezetimibe treatment. Conclusion: Ezetimibe alone reduces PHTG by blocking both the absorption of cholesterol and the intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, resulting in the reduction of the formation of ApoB-48 which is necessary for the ApoB48-containing lipoprotein production in the small intestines.

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Sandoval JC, Nakagawa-Toyama Y, Masuda D, Tochino Y, Nakaoka H, Kawase R et al. Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia. Journal of atherosclerosis and thrombosis. 2010 Jan 1;17(9):914-924. https://doi.org/10.5551/jat.4929