Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducingNpc1l1expression.
The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded byCreb3l3) 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.



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.



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 regulatesNpc1l1expression. Conversely, CREBH null mice exhibited higher intestinalNpc1l1expression, elevated plasma and hepatic cholesterol, and lower fecal output.



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.
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Takuya
T
Kikuchi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Kana
K
Orihara
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Fusaka
F
Oikawa
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Song-Iee
SI
Han
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Motoko
M
Kuba
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Kanako
K
Okuda
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Aoi
A
Satoh
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Yoshinori
Y
Osaki
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Yoshinori
Y
Takeuchi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Yuichi
Y
Aita
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Takashi
T
Matsuzaka
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Hitoshi
H
Iwasaki
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Shigeru
S
Yatoh
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Motohiro
M
Sekiya
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Naoya
N
Yahagi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Hiroaki
H
Suzuki
Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Niigata 951-8510, Japan.
Hirohito
H
Sone
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: ynakagawa@md.tsukuba.ac.jp.
Yoshimi
Y
Nakagawa
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Nobuhiro
N
Yamada
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan. Electronic address: hshimano@md.tsukuba.ac.jp.
Hitoshi
H
Shimano
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D002791:Cholesterol, Dietary / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism*; D008074:Lipoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; C533813:CREB3L3 protein, human; D002791:Cholesterol, Dietary; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D008074:Lipoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse
ABCG5/8, adenosine triphosphate-binding cassette transporter G5/G8; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Abca1, ATP-binding cassette, sub-family A1; Apoa4, apolipoprotein A-IV; CREBH; CREBH, cyclic AMP-responsive element-binding protein H; Cholesterol; Cpt1a, carnitine palmitoyltransferase 1a, liver; Cyp7a1, cytochrome P450, family 7, subfamily a, polypeptide 1; ER, endoplasmic reticulum; FGF21, fibroblast growth factor 21; FXR, Farnesoid X receptor; Intestine; LD, lithogenic diet; LPL, lipoprotein lipase; LXR, liver X receptor; NEFA, non-esterified fatty acids; NPC1L1, Nieman Pick C1-like 1; Npc1l1; PPARα, proliferator activated receptor alpha; RCT, reverse cholesterol transport; SREBP, sterol regulatory element-binding protein; Shp, small heterodimer partner; Srb1, scavenger receptor class B, member 1; Srebf, sterol regulatory element-binding factor; TG, triglyceride; WT, wild type