The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)

García‐Calvo, Margarita; Lisnock, JeanMarie; Bull, Herbert G.; Hawes, Brian E.; Burnett, Duane A.; Braun, Matthew P.; Crona, James H.; Davis, Harry R.; Dean, Dennis C.; Detmers, Patricia A.; Graziano, Michael P.; Hughes, A. Meredith; MacIntyre, D. Euan; Ogawa, Anthony K.; O’Neill, Kim; Iyer, Sai Prasad N.; Shevell, Diane E.; Smith, Marsha M.; Tang, Yui S.; Makarewicz, Amanda M.; Ujjainwalla, Feroze; Altmann, Scott; Chapman, Kevin T.; Thornberry, Nancy A.

doi:10.1073/pnas.0500269102

Cited by 682 publications

(473 citation statements)

References 32 publications

(30 reference statements)

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“…New evidence strongly suggests that a transporterfacilitated mechanism is involved. Interindividual differences and interstrain variations in the efficiency of intestinal cholesterol absorption (195,196) support this suggestion, as does the discovery that multiple genes (4,14,106,113) participate in the regulation of cholesterol absorption and several molecules appear to inhibit it (59).…”

Section: Cholesterolmentioning

confidence: 68%

Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

622

460

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Our knowledge of the uptake and transport of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have identified several new mechanisms by which lipids are taken up by enterocytes and packaged as chylomicrons for export into the lymphatic system or clarified the actions of mechanisms previously known to participate in these processes. Fatty acids are taken up by enterocytes involving protein-mediated as well as proteinindependent processes. Net cholesterol uptake depends on the competing activities of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of lipid hydrolysis, the active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral lipids and utilized within the endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins are secreted from the basolateral side of the enterocyte. apoB and MTP are known to be central to the efficient assembly and secretion of lipoproteins. In recent studies, investigators found that cholesterol, phospholipids, and vitamin E can also be secreted from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential as targets for the development of drugs that can suppress cholesterol absorption, thereby reducing the risk of hypercholesterolemia and cardiovascular disease.intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vitamins; microsomal triglyceride transfer protein DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolar lipids (32, 33). Triacylglycerol (TAG) is the dominant fat in the diet, contributing 90 -95% of the total energy derived from dietary fat. Dietary fats also include phospholipids (PLs), sterols (e.g., cholesterol), and many other lipids (e.g., fatsoluble vitamins). The predominant PL in the intestinal lumen is phosphatidylcholine (PC), which is derived mostly from bile (10 -20 g/day in humans) but also from the diet (ϳ1-2 g/day). The predominant dietary sterols are cholesterol (mostly of animal origin) and ␤-sitosterol (the major plant sterol). Although ␤-sitosterol accounts for 25% of dietary sterols, it is not absorbed by humans under physiological conditions.Researchers have been investigating the various steps involved in lipid digestion, absorption, and metabolism to identify factors that could serve as targets for the development of drugs capable of reducing the risk of lipid-associated disorders, including dyslipidemias and cardiovascular disease. In so doing, they have explored key aspects of lipid digestion hydrolysis, emulsification, and micelle formation. They have also explored key issues of absorption, e.g., the uptake of the products of lipid hydrolysis by enterocytes (the epithelial cells lining the walls of the intestinal lumen) and their transport to intracellular compartments, where fatty acids and sterols are...

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Section: Cholesterolmentioning

confidence: 68%

Intestinal lipid absorption

Iqbal¹,

Hussain²

2009

American Journal of Physiology-Endocrinology and Metabolism

622

460

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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. It is now believed that intestinal cholesterol absorption is regulated by two transporters, NPC1L1 and ABCG5/8.…”

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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“…Niemann-Pick C1-like 1 (NPC1L1) plays a pivotal role in cholesterol incorporation in enterocytes [6]. Ezetimibe, a potent inhibitor of cholesterol absorption, inhibits NPC1L1-dependent cholesterol transport at the brush border of the intestine and the liver [6].…”

Section: Introductionmentioning

confidence: 99%

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

et al. 2014

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Aims/hypothesis The cholesterol absorption inhibitor ezetimibe has been shown to ameliorate non-alcoholic fatty liver disease (NAFLD) pathology in a single-armed clinical study and in experimental animal models. In this study, we investigated the efficacy of ezetimibe on NAFLD pathology in an open-label randomised controlled clinical trial. Methods We had planned to enrol 80 patients in the trial, as we had estimated that, with this sample size, the study would have 90% power. The study intervention and enrolment were discontinued because of the higher proportion of adverse events (significant elevation in HbA 1c ) in the ezetimibe group than in the control group. Thirty-two patients with NAFLD were enrolled and randomised (allocation by computer program). Ezetimibe (10 mg/day) was given to 17 patients with NAFLD for 6 months. The primary endpoint was change in serum aminotransferase level. Secondary outcomes were change in liver histology (12 control and 16 ezetimibe patients), insulin sensitivity including a hyperinsulinaemic-euglycaemic clamp study (ten control and 13 ezetimibe patients) and hepatic fatty acid composition (six control and nine ezetimibe patients). Hepatic gene expression profiling was completed in 15 patients using an Affymetrix gene chip. Patients and the physician in charge knew to which group the patient had been allocated, but people carrying out measurements or examinations were blinded to group. Results Serum total cholesterol was significantly decreased in the ezetimibe group. The fibrosis stage and ballooning score were also significantly improved with ezetimibe treatment. However, ezetimibe treatment significantly increased HbA 1c and was associated with a significant increase in hepatic longchain fatty acids. Hepatic gene expression analysis showed coordinate downregulation of genes involved in skeletal muscle development and cell adhesion molecules in the ezetimibe treatment group, suggesting a suppression of stellate cell development into myofibroblasts. Genes involved in the L-carnitine pathway were coordinately downregulated by ezetimibe treatment and those in the steroid metabolism pathway upregulated, suggestive of impaired oxidation of long-chain fatty acids. Conclusions/interpretation Ezetimibe improved hepatic fibrosis but increased hepatic long-chain fatty acids and HbA 1c in patients with NAFLD. These findings shed light on previously unrecognised actions of ezetimibe that should be examined further in future studies.

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The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)

Cited by 682 publications

References 32 publications

Intestinal lipid absorption

Intestinal lipid absorption

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

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

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