Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

Xie, Ping; Zhu, Hongling; Lin, Jen‐Der; Ma, Yinyan; Tang, Weiqing; Wang, Youlin; Xue, Bingzhong; Shi, Hang; Yu, Liqing

doi:10.1016/j.atherosclerosis.2014.09.036

Cited by 24 publications

(12 citation statements)

References 50 publications

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“…3, C and D). This is consistent with a previous report demonstrating that intestinal NPC1L1 is a major determinant of plasma VLDL/LDL cholesterol levels in LDLR-deficient mice (Xie et al, 2014). In addition, we revealed that, besides intestinal NPC1L1, hepatic NPC1L1 also contributes to increased VLDL/LDL lipid levels (Fig.…”

Section: Discussionsupporting

confidence: 93%

Hepatic Expression of Niemann-Pick C1-Like 1, a Cholesterol Reabsorber from Bile, Exacerbates Western Diet–Induced Atherosclerosis in LDL Receptor Mutant Mice

Yamamoto

Yamanashi

Takada

et al. 2019

Molecular Pharmacology

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Westernization of dietary habits increases lipid intake and is responsible for increased numbers of patients with atherosclerotic diseases. Niemann-Pick C1-Like 1 (NPC1L1)-a cholesterol importer-plays a crucial role in dietary cholesterol absorption in the intestine and is closely associated with several lipid-related diseases, including atherosclerosis. NPC1L1 is highly expressed in the liver and intestine in humans, whereas NPC1L1 expression is low in the rodent liver. Due to species differences in the tissue distribution of NPC1L1, there are limited studies on the pathophysiological role of hepatic NPC1L1, a cholesterol reabsorber from bile. In the present study, to explore whether hepatic NPC1L1 is involved in the development/ progression of atherosclerosis, we compared four kinds of atherosclerosis mouse models with different expression levels of NPC1L1 in the intestinal and liver tissues in a genetic background of dysfunctional low-density lipoprotein receptor mutation. Western diet (WD)-induced hyperlipidemia and atherosclerotic plaque formation were more severe in mice expressing NPC1L1 in both the liver and intestine (plasma cholesterol, 839.5 mg/dl; plaque area, 29.5% of total aorta), compared with mice expressing NPC1L1 only in the intestine (plasma cholesterol, 573.1 mg/dl; plaque area, 13.3% of total aorta). Such hepatic NPC1L1-mediated promotion of hyperlipidemia and atherosclerosis was not observed in mice not expressing intestinal NPC1L1 and mice treated with ezetimibe, an NPC1L1 inhibitor used clinically for dyslipidemia. These results suggested that hepatic NPC1L1 promotes WD-induced dyslipidemia and atherosclerosis in concert with intestinal NPC1L1. Our findings provide novel insights into the pathophysiological importance of hepatic NPC1L1 in development/progression of atherosclerosis. SIGNIFICANCE STATEMENTNiemann-Pick C1-Like 1 (NPC1L1) protein, a cholesterol importer and a molecular target of ezetimibe clinically used for dyslipidemia, is highly expressed not only in the intestine, but also in the liver in humans, although the pathophysiological importance of hepatic NPC1L1 in atherosclerotic diseases remained unclear. By using novel mouse models to separately analyze the effects of hepatic and intestinal NPC1L1 on the development/progression of atherosclerosis, we first demonstrated that hepatic NPC1L1 accelerates Western diet-induced atherosclerotic plaque formation in an intestinal NPC1L1-dependent and an ezetimibe-sensitive manner.

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Section: Discussionsupporting

confidence: 93%

Hepatic Expression of Niemann-Pick C1-Like 1, a Cholesterol Reabsorber from Bile, Exacerbates Western Diet–Induced Atherosclerosis in LDL Receptor Mutant Mice

Yamamoto

Yamanashi

Takada

et al. 2019

Molecular Pharmacology

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“…Ezetimibe (trademark name Zetia), the first drug approved after statins, is a potent intestinal cholesterol absorption inhibitor that targets NPC1L1 [ 20 , 41 ]. This therapy also presents good results in terms of decreasing LDL-c [ 42 ].…”

Section: Hypercholesterolemia and The Actual Treatmentmentioning

confidence: 99%

Brown Algae Potential as a Functional Food against Hypercholesterolemia: Review

André

Pacheco

Bourbon

et al. 2021

Foods

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Brown algae have been part of the human diet for hundreds of years, however, in recent years, commercial and scientific interest in brown algae has increased due to the growing demand for healthier diet by the world population. Brown algae and its metabolites, such as carotenoids, polysaccharides, phlorotannins, and proteins, have been associated with multiple beneficial health effects for different diseases, such as cardiovascular diseases, one of the main causes of death in Europe. Since high blood cholesterol levels are one of the major cardiovascular risks, this review intends to provide an overview of current knowledge about the anti-hypercholesterolemic effect of different brown algae species and/or their isolated compounds.

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“…Cholesterol absorption in the gut has been studied extensively because of its significant positive correlation with plasma cholesterol concentration, which, in turn, is a major risk factor for atherosclerosis [1], [2]. Cholesterol absorption depends on transport from the intestinal lumen across enterocytes into the plasma [3].…”

Section: Introductionmentioning

confidence: 99%

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

Kikuchi

Orihara

Oikawa

et al. 2016

Molecular Metabolism

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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.

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Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels

Cited by 24 publications

References 50 publications

Hepatic Expression of Niemann-Pick C1-Like 1, a Cholesterol Reabsorber from Bile, Exacerbates Western Diet–Induced Atherosclerosis in LDL Receptor Mutant Mice

Hepatic Expression of Niemann-Pick C1-Like 1, a Cholesterol Reabsorber from Bile, Exacerbates Western Diet–Induced Atherosclerosis in LDL Receptor Mutant Mice

Brown Algae Potential as a Functional Food against Hypercholesterolemia: Review

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

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