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.
Keywords: 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.