Intestinal cholesterol transport proteins: an update and beyond.
ABSTRACT Various studies have delineated the causal role of dietary cholesterol in atherogenesis. Strategies have thus been developed to minimize cholesterol absorption, and cholesterol transport proteins found at the apical membrane of enterocytes have been extensively investigated. This review focuses on recent progress related to various brush-border proteins that are potentially involved in alimentary cholesterol transport.
Molecular mechanisms responsible for dietary cholesterol and plant sterol uptake have not been completely defined. Growing evidence, however, supports the concept that several proteins are involved in mediating intestinal cholesterol transport, including SR-BI, NPC1L1, CD36, aminopeptidase N, P-glycoprotein, and the caveolin-1/annexin-2 heterocomplex. Other ABC family members (ABCA1 and ABCG5/ABCG8) act as efflux pumps favoring cholesterol export out of absorptive cells into the lumen or basolateral compartment. Several of these cholesterol carriers influence intracellular cholesterol homeostasis and are controlled by transcription factors, including RXR, LXR, SREBP-2 and PPARalpha. The lack of responsiveness of NPC1L1-deficient mice to ezetimibe suggests that NPC1L1 is likely to be the principal target of this cholesterol-lowering drug.
The understanding of the role, genetic regulation and coordinated function of proteins mediating intestinal cholesterol transport may lead to novel ways of treating cardiovascular disease.
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ABSTRACT: Lipids serve essential functions in cells as signaling molecules, membrane components, and sources of energy. Defects in lipid metabolism are implicated in a number of pandemic human diseases, including diabetes, obesity, and hypercholesterolemia. Many aspects of how fatty acids and cholesterol are absorbed and processed by intestinal cells remain unclear and present a hurdle to developing approaches for disease prevention and treatment. Numerous studies have shown that the zebrafish is an excellent model for vertebrate lipid metabolism. In this chapter, we review studies that employ zebrafish to better understand lipid signaling and metabolism.Methods in cell biology 01/2011; 101:111-41. DOI:10.1016/B978-0-12-387036-0.00005-0 · 1.44 Impact Factor
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ABSTRACT: This study was conducted to elucidate the mechanism underlying the hypolipidemic action of karaya saponin or Rhodobacter (R.) capsulatus. A total of 40 laying hens (20-week-old) were assigned into four dietary treatment groups and fed a basal diet (as a control) or basal diets supplemented with either karaya saponin, R. capsulatus, or both for 60 days. The level of serum low-density-lipoprotein cholesterol and the levels of cholesterol and triglycerides in the serum, liver, and egg yolk were reduced by all the supplementations (P < .05). Liver bile acid concentration and fecal concentrations of cholesterol, triacylglycerol, and bile acid were simultaneously increased by the supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus (P < .05). The supplementation of karaya saponin, R. capsulatus, and the combination of karaya saponin and R. capsulatus suppressed the incorporation of (14)C from 1-(14)C-palmitic acid into the fractions of total lipids, phospholipids, triacylglycerol, and cholesterol in the liver in vitro (P < .05). These findings suggest that the hypocholesterolemic effects of karaya saponin and R. capsulatus are caused by the suppression of the cholesterol synthesis and the promotion of cholesterol catabolism in the liver.Cholesterol 06/2010; 2010:272731. DOI:10.1155/2010/272731
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ABSTRACT: Background Several transporter proteins regulate intestinal cholesterol absorption. Of these proteins, NPC1L1 plays a major role to this process. Fatty acids (FA) modulate cholesterol absorption by a mechanism that remains unknown. Objectives To evaluate the effect of saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids on the expression of NPC1L1 in human enterocytes in vitro and to study the role of the nuclear receptors PPARγ PPARδ, LXR and RXR. Methods Caco-2/TC-7 enterocytes were incubated for 24 h with non-cytotoxic concentrations (50, 100, 200 and 300 μM) of the different FA. NPC1L1 gene expression was analyzed by quantitative rtPCR and the protein present in enterocyte membranes was analyzed by western blot. Results NPC1L1 mRNA levels were reduced 35 to 58% by the n-3 PUFA, EPA and DHA (p < 0.05). LA (n-6), PA, and OA did not affect NPC1L1 mRNA expression. ABCA1 mRNA levels were reduced 44 to 70% by n-6 AA and 43 to 55% by n-3 EPA (p < 0.05). LXR and LXR+RXR agonists decreased NPC1L1 mRNA expression by 28 and 57%, respectively (p < 0.05). A concentration of 200 μM of EPA and DHA decreased NPC1L1 protein expression in enterocyte membranes by 58% and 59%, respectively. Conclusions We have demonstrated that the PUFAs n-3 EPA and DHA down-regulate NPC1L1 mRNA expression in vitro. In addition, PUFA also down-regulate NPC1L1 protein expression in enterocyte membranes. LXR and RXR activation induced a similar repression effect. The lipid lowering effect of n-3 PUFA could be mediated in part by their action at the NPC1L1 gene level.Clínica e Investigación en Arteriosclerosis 10/2008; 20(5). DOI:10.1016/S0214-9168(08)75907-2