Molecular mechanisms of ezetimibe-induced attenuation of postprandial hypertriglyceridemia.
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.
Sandoval
José C
JC
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Nakagawa-Toyama
Yumiko
Y
Masuda
Daisaku
D
Tochino
Yoshihiro
Y
Nakaoka
Hajime
H
Kawase
Ryota
R
Yuasa-Kawase
Miyako
M
Nakatani
Kazuhiro
K
Inagaki
Miwako
M
Tsubakio-Yamamoto
Kazumi
K
Ohama
Tohru
T
Matsuyama
Akifumi
A
Nishida
Makoto
M
Ishigami
Masato
M
Komuro
Issei
I
Yamashita
Shizuya
S
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
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