論文

国際誌
2016年11月

Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression.

Molecular metabolism
  • Takuya Kikuchi
  • ,
  • Kana Orihara
  • ,
  • Fusaka Oikawa
  • ,
  • Song-Iee Han
  • ,
  • Motoko Kuba
  • ,
  • Kanako Okuda
  • ,
  • Aoi Satoh
  • ,
  • Yoshinori Osaki
  • ,
  • Yoshinori Takeuchi
  • ,
  • Yuichi Aita
  • ,
  • Takashi Matsuzaka
  • ,
  • Hitoshi Iwasaki
  • ,
  • Shigeru Yatoh
  • ,
  • Motohiro Sekiya
  • ,
  • Naoya Yahagi
  • ,
  • Hiroaki Suzuki
  • ,
  • Hirohito Sone
  • ,
  • Yoshimi Nakagawa
  • ,
  • Nobuhiro Yamada
  • ,
  • Hitoshi Shimano

5
11
開始ページ
1092
終了ページ
1102
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.molmet.2016.09.004

OBJECTIVE: The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown. METHODS: To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions. RESULTS: Plasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann-Pick C1-like 1 (Npc1l1), a rate-limiting transporter mediating intestinal cholesterol absorption, was reduced in the small intestine of CREBH Tg mice. Adenosine triphosphate-binding cassette transporter A1 (Abca1), Abcg5/8, and scavenger receptor class B, member 1 (Srb1) expression levels were also reduced in CREBH Tg mice. Promoter assays revealed that CREBH directly regulates Npc1l1 expression. Conversely, CREBH null mice exhibited higher intestinal Npc1l1 expression, elevated plasma and hepatic cholesterol, and lower fecal output. CONCLUSION: Intestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia.

リンク情報
DOI
https://doi.org/10.1016/j.molmet.2016.09.004
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/27818935
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081412
ID情報
  • DOI : 10.1016/j.molmet.2016.09.004
  • PubMed ID : 27818935
  • PubMed Central 記事ID : PMC5081412

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