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

Abstract

ObjectiveThe 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.MethodsTo 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.ResultsPlasma 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.ConclusionIntestinal 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.

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

“…Taken together, CREB3L3 deletion in the small intestine contributes to hyperlipidemia. Conversely, as we previously reported, intestinal CREB3L3-overexpressed mice exhibited the suppression of plasma TC levels when fed the same diet via the suppression of cholesterol absorption in the intestine ( Kikuchi et al, 2016 ). These findings indicate that hepatic CREB3L3 regulates TG metabolism, and that intestinal CREB3L3 regulates cholesterol and TG absorption in the small intestine, further suggesting that CREB3L3 regulates systemic lipid metabolism in enterohepatic circulation.…”

Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption

“…Binding motifs for several factors, including SREBFs, were identified in these regions ( Figure 6A, left). Since multiple SREs were detected at the Npc1l1 gene promoter, intestinal expression of Npc1l1 is activated by SREBF2 and to a much lesser extent by SREBF1 [35][36][37] , and SREBF2 expression strongly correlates with NPC1L1 expression in hyperlipidemia patients 38 , we focused mechanistic studies on SREBF2.…”

CREBH Regulates Systemic Glucose and Lipid Metabolism

“…On feeding an AHF diet, mice overexpressing the active form of CREBH in the intestine exhibited an apparent reduction of gallstone formation in gall bladders and plasma cholesterol levels compared with those in WT mice [ 20 ]. CREBH increased cholesterol levels in feces and reduced intestinal cholesterol levels, thereby indicating that CREBH suppresses the absorption of cholesterol from the diet in the small intestine [ 20 ]. Niemann Pick C1-like 1 (NPC1L1) is a protein localized at the brush border membrane of the enterocytes, mediating cholesterol absorption into the enterocytes.…”

“…Ezetimibe is a drug for hyperlipidemia that inhibits cholesterol absorption by blocking NPC1L1 intestinal transporters, resulting in a decrease in plasma cholesterol levels. CREBH reduces Npc1l1 expression, leading to a reduction in cholesterol absorption from the small intestine and in plasma cholesterol levels [ 20 ]. CREBH might be a therapeutic target for the treatment of hyperlipidemia by inhibiting cholesterol absorption.…”