Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

Altmann, Scott; Davis, Harry R.; Zhu, Lian; Yao, Xiangdong; Hoos, Lizbeth; Tetzloff, Glen; Iyer, Sai Prasad N.; Maguire, Maureen; Головко, Андрей; Zeng, Ming; Wang, Luquan; Murgolo, Nicholas; Graziano, Michael P.

doi:10.1126/science.1093131

Cited by 1,552 publications

(1,378 citation statements)

References 30 publications

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“…Cholesterol removal from the endosome depends on the NPC1 protein, which contains a sterol-sensing domain. Like its plasma membrane counterpart NPC1L1 [37 ], it transports cholesterol (and possibly sphingolipids [38]) towards the cytosol by a mechanism that is unclear but may involve vesiculation. Cholesterol also modulates vesicular traffic at and after the early endosomes via annexin II [39,40].…”

Section: Selective Endocytosismentioning

confidence: 99%

Membrane lipids and vesicular traffic

Meer

Sprong

2004

Current Opinion in Cell Biology

156

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Lipids were long considered to be passive passengers of carrier vesicles with the single role of sealing the transport container. We now know that specific phospholipids are required for efficient fusion, while others facilitate budding and fission. Moreover, the various polyphosphoinositides assist in the recruitment from the cytosol of proteins of the transport machinery. Finally, the segregation of membrane lipids into different fluid phases appears to serve as a 'lipid raft' mechanism for protein sorting at various stages of the secretory and endocytic pathways. The current challenge is to understand how proteins control the metabolism and subcellular localization, and thereby the activity, of the various lipids.

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Section: Selective Endocytosismentioning

confidence: 99%

Membrane lipids and vesicular traffic

Meer

Sprong

2004

Current Opinion in Cell Biology

156

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“…[2][3][4][5][6][7][8] It is also the molecule target for the new cholesterol-lowering agent, ezetimibe. 9 Human NPC1L1 is expressed mainly in the intestine and liver and is responsible for transporting cholesterol from intestinal lumen to enterocytes.…”

Section: Introductionmentioning

confidence: 99%

The g.−762T>C polymorphism of the NPC1L1 gene is common in Chinese and contributes to a higher promoter activity and higher serum cholesterol levels

et al. 2009

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Niemann-Pick type C1-like 1 (NPC1L1) protein is responsible for intestinal cholesterol absorption. The aim of the study was to identify genetic polymorphisms of the NPC1L1 gene as well as their functional significance. The method involved screening of promoter and coding regions of the NPC1L1 gene for genetic polymorphisms by direct DNA sequencing of genomic DNA from 50 individuals. Functional studies on promoter polymorphisms were performed using luciferase assay. Association between the polymorphisms and serum cholesterol levels were investigated in 224 individuals. The results showed that in total, 11 single nucleotide polymorphisms were identified. Among them, a promoter polymorphism, g.À762T4C, and a synonymous polymorphism, g.1679C4G, were common (34 and 36%, respectively). These two polymorphisms were highly linked (D¢ value¼0.7459, P-value o0.00001). For the g.À762T4C promoter polymorphism, luciferase assay in HepG2 cell line demonstrated that the À762C allele had a significantly higher promoter activity than the À762T allele (1.30 ± 0.22 vs 0.37 ± 0.06, 3.5-fold, Po0.05). We also showed that the NPC1L1 promoter activity was downregulated by cholesterol content in both genotypes. When association studies were performed, we found that À762C allele was associated with significantly higher serum total cholesterol and LDL-cholesterol content levels in a recessive model (LDL-cholesterol value¼131.2 ± 8.1 vs 116.4 ± 2.2 mg dl -1 ; total cholesterol value¼214.7 ± 9.0 mg dl -1 vs 196.9 ± 2.6, P-value o0.05, n¼224). In conclusion, the C allele at À762 position of the NPC1L1 gene was common in people of Chinese ethnicity. The À762C allele had a higher promoter activity and was associated with a higher serum total cholesterol and LDL-cholesterol level.

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“…The NiemannPick disease, type C1-like 1 (NPC1L1) protein and gene have recently been described following the discovery of the drug ezetimibe, which lowers serum cholesterol by reducing cholesterol absorption. Ezetimibe was found to work by inhibiting NPC1L1 [17]. Thus this protein appears to play an important role in regulating intestinal cholesterol absorption [18].…”

Section: Introductionmentioning

confidence: 99%

Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann–Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein

et al. 2006

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Aims/hypothesis: The aim of the present study was to examine the relationship between chylomicron composition and expression of genes that regulate chylomicron production in the intestine. We examined expression of the following: (1) Niemann-Pick C1-like 1 (NPC1L1), which regulates cholesterol absorption; (2) ATP-binding cassette transporters G5 and G8 (ABCG5, ABCG8), which regulate cholesterol homeostasis through their ability to excrete enterocyte cholesterol back into the lumen of the intestine; and (3) microsomal triglyceride transfer protein (MTTP), which packages the chylomicron particle by assembling cholesterol, triglyceride, phospholipids and apolipoprotein B48. Subjects, materials and methods: Type 2 diabetic (26) and non-diabetic (21) patients were examined. Levels of NPC1L1, ABCG5 and ABCG8 and MTTP mRNA were measured in duodenal biopsies by real-time PCR. Lipoproteins were isolated by sequential ultracentrifugation. Results: Diabetic patients had more NPC1L1 mRNA than the control subjects (p<0.02). Expression of ABCG5 and ABCG8 mRNA was lower in the diabetic patients (p<0.05) and MTTP expression was increased (p<0.05). There was a positive correlation between NPLC1L1 and MTTP mRNA (p<0.01) and a negative correlation between NPC1L1 and ABCG5 mRNA (p<0.001). Diabetic patients on statin therapy had increased ABCG5 and ABCG8 mRNA compared to those not on statin (p<0.02 and p<0.05) and less MTTP mRNA than those not on statin (p<0.05). Conclusions/ interpretation: This study demonstrates that in type 2 diabetes there are important alterations to the expression of intestinal genes that regulate cholesterol absorption and chylomicron synthesis. In diabetic patients statin therapy is associated with reduced MTTP expression and increased ABCG5 and ABCG8 mRNA. The study suggests new mechanisms to explain postprandial diabetic dyslipidaemia and the beneficial effect of statins.

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Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption

Cited by 1,552 publications

References 30 publications

Membrane lipids and vesicular traffic

Membrane lipids and vesicular traffic

The g.−762T>C polymorphism of the NPC1L1 gene is common in Chinese and contributes to a higher promoter activity and higher serum cholesterol levels

Messenger RNA levels of genes involved in dysregulation of postprandial lipoproteins in type 2 diabetes: the role of Niemann–Pick C1-like 1, ATP-binding cassette, transporters G5 and G8, and of microsomal triglyceride transfer protein

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