title: Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia.
abstract: OBJECTIVE
  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 atten-uate 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 chromatogra-phy (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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: José C
authors.initials: JC
authors.lastname: Sandoval
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nakagawa-Toyama
authors.forename: Daisaku
authors.initials: D
authors.lastname: Masuda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tochino
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakaoka
authors.forename: Ryota
authors.initials: R
authors.lastname: Kawase
authors.forename: Miyako
authors.initials: M
authors.lastname: Yuasa-Kawase
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakatani
authors.forename: Miwako
authors.initials: M
authors.lastname: Inagaki
authors.forename: Kazumi
authors.initials: K
authors.lastname: Tsubakio-Yamamoto
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohama
authors.forename: Akifumi
authors.initials: A
authors.lastname: Matsuyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishida
authors.forename: Masato
authors.initials: M
authors.lastname: Ishigami
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D053283:Apolipoprotein B-48 / Q000378:metabolism; D001384:Azetidines / Q000494:pharmacology*; D001483:Base Sequence; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics; D002914:Chylomicrons / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D000069438:Ezetimibe; D050612:Fatty Acid Transport Proteins / Q000235:genetics; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D007408:Intestinal Absorption / Q000187:drug effects; D008079:Lipoproteins, VLDL / Q000097:blood; D008196:Lymph / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019518:Postprandial Period; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014304:Triolein / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D053283:Apolipoprotein B-48; D001384:Azetidines; D018955:CD36 Antigens; D002914:Chylomicrons; D017931:DNA Primers; D050612:Fatty Acid Transport Proteins; D050556:Fatty Acid-Binding Proteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014280:Triglycerides; D014304:Triolein; D000069438:Ezetimibe