Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse

Valasek, Mark A.; Clarke, Stephen; Repa, Joyce J.

doi:10.1194/jlr.m700345-jlr200

Cited by 104 publications

(85 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It could result from increased intrahepatic cholesterol concentrations and subsequently reduced SREBP2 (sterol regulatory element-binding protein 2) activity on PCSK9 gene transcription (5,17 ). However, fenofibrate has been shown in mice to reduce the intestinal absorption of dietary cholesterol, which actually depletes intrahepatic cholesterol stores (27 ). Together with our results showing reduced PCSK9 secretion from fenofibric acid-treated hepatoma cells, this strongly suggests that fenofibrate negatively modulates PCSK9 expression and/or secretion directly at the hepatocyte level.…”

Section: Discussionsupporting

confidence: 73%

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

et al. 2008

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 73%

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

et al. 2008

View full text Add to dashboard Cite

show abstract

“…HFHC diet decreases expression of NPC1L1 presumably because of its high fat content ( 50,55 ). The resultant increase in BBM cholesterol content and ABCG5/G8 cholesterol effl ux activity under HFHC diet conditions leads to a back fl ux of cholesterol to BSM in the lumen of the small intestine so that the net level of cholesterol fl ux into the BBM becomes sensitive to the scavenger receptor-mediated infl ux contribution ( Fig.…”

Section: Downloaded Frommentioning

confidence: 99%

Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption

Nguyen

Drover

Knöpfel

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

The effi ciency of absorption of dietary cholesterol in the small intestine affects plasma LDL cholesterol levels and thereby cardiovascular disease risk ( 1, 2 ). Consequently, there is great interest in understanding the mechanism of intestinal cholesterol absorption and inhibiting the process to reduce plasma cholesterol levels. Ezetimibe is such an inhibitor whose target is the protein NiemannPick C1-like 1 (NPC1L1) ( 3, 4 ); the importance of this protein in cholesterol absorption is refl ected by the fact that the absorption effi ciency is greatly reduced in mice lacking the gene encoding NPC1L1 ( 5, 6 ). Experiments with knockout and transgenic mice have variously demonstrated that acylCoA:cholesterol-acyltransferase-2 (ACAT-2) ( 7-9 ) and ATP binding cassette half transporters G5 and G8 (ABCG5/G8) ( 10-13 ) also play critical roles in the cholesterol absorption pathway. The above proteins are all involved in enterocyte cholesterol homeostasis ( 14, 15 ), but factors such as lipase activity and bile salt availability in the earlier digestive phase of the pathway are also critical (for recent reviews, see Refs. 14 and 16 ). Current understanding of the proteins and mechanisms controlling the uptake of cholesterol from the lumen of the small intestine into and across the brush border membrane (BBM) is relatively limited. Here, we distinguish between cholesterol uptake and cholesterol absorption, defi ning the former as the process of cholesterol transfer from the donor particle in the lumen of the small intestine to the BBM and the latter as the cascade of transport steps Press, May 19, 2009 DOI 10.1194 Abbreviations: ABCG5/G8, ATP binding cassette half transporters G5 and G8; ACAT-2, acylCoA:cholesterol-acyltransferase-2; BBM, brush border membrane; BBMV, brush border membrane vesicle; BSM, mixed bile salt micelle; CD36, cluster determinant 36; HFHC, high-fat/ high-cholesterol diet; NPC1L1, Niemann Pick C1-Like 1; SR-BI, scavenger receptor class B, type 1; SUV, small unilamellar vesicle; WT, wild type. Published, JLR Papers in

show abstract

“…LXRs also play a central role in the transcriptional response to dietary cholesterol in mice, and directly or indirectly control a number of genes that are related to DHR96-regulated genes, including ABCG1, LPL, steroylCoA desaturase, NPC1, and NPC2 (Maxwell et al 2003;Rigamonti et al 2005;Kalaany and Mangelsdorf 2006). Finally, like DHR96, LXRs repress NPC1L1 expression, although it is not clear whether this regulation is direct (Duval et al 2006;Valasek et al 2007). Taken together, these results indicate that DHR96 and mammalian LXRs act through similar regulatory pathways to control cholesterol homeostasis.…”

Section: Dhr96 Represents An Ancestral Regulator Of Cholesterol Metabmentioning

confidence: 99%

“…Mouse mutants for NPC1L1 display significantly reduced levels of cholesterol absorption and are insensitive to treatment with the anti-hypercholesterolemia drug ezetimibe, which acts as a specific NPC1L1 inhibitor (Davis et al 2008). Another major regulator of cholesterol homeostasis is the liver X receptor a (LXRa) nuclear receptor, which binds cholesterol metabolites and regulates the transcription of genes that control cholesterol transport and metabolism, including NPC1L1 (Duval et al 2006;Kalaany and Mangelsdorf 2006;Valasek et al 2007). …”

mentioning

confidence: 99%

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Horner¹,

Pardee²,

et al. 2009

View full text Add to dashboard Cite

Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis. Cholesterol is an essential component of cell membranes that influences the permeability and fluidity of the lipid bilayer. Cholesterol also acts as a precursor for steroid hormone biosynthesis and contributes to cell-cell signaling pathways. These critical cellular functions are supported by regulatory mechanisms that maintain normal cholesterol levels and prevent hypercholesterolemia, which is a major risk factor for cardiovascular disease in humans. Cholesterol homeostasis in vertebrates is achieved primarily through de novo synthesis and dietary uptake (Ikonen 2008). Although extensive studies have defined a central role for the sterol regulatory elementbinding protein (SREBP) family of transcription factors in controlling cholesterol synthesis (Brown and Goldstein 1997), the mechanisms that regulate dietary cholesterol absorption remain more poorly understood. One central component of this pathway is the Niemann-Pick C1-like 1 gene NPC1L1, which encodes a plasma membrane protein that mediates the uptake of dietary cholesterol by the intestine (Wang 2007;Ge et al. 2008). Mouse mutants for NPC1L1 display significantly reduced levels of cholesterol absorption and are insensitive to treatment with the anti-hypercholesterolemia drug ezetimibe, which acts as a specific NPC1L1 inhibitor (Davis et al. 2008). Another major regulator of cholesterol homeostasis is the liver X receptor a (LXRa) nuclear receptor, which binds cholesterol metabolites and regulates the transcription of genes that control cholesterol transport and metabolism, including NPC1L1 (Duval et al. 2006;Kalaany and Mangelsdorf 2006;Valasek et al. 2007).We used the fruit fly, Drosophila, as a model system to study the regulation of cholesterol homeostasis. Unlike vertebrates, insects are cholesterol auxotrophs that are unable to synthesize this essential compound (Va'nt Hoog 1936). Little is known, however, about the mechanisms that regulate the uptake of dietary cholesterol in Drosophila. A recent study showed that the fly ortholog of NPC1L1, npc1b, is expressed specifically in the midgut and is essential for dietary cholesterol absorption (Voght et al. 2007). Other NPC disease gene homologs in Drosophila also contribute to cholesterol homeostasis. The Drosophila ortholog of vert...

show abstract

Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse

Cited by 104 publications

References 57 publications

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

Plasma PCSK9 Concentrations Correlate with LDL and Total Cholesterol in Diabetic Patients and Are Decreased by Fenofibrate Treatment

Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption

The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Contact Info

Product

Resources

About