Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461

Salisbury, Brian; Davis, Harry R.; Burrier, Robert E.; Burnett, Duane A.; Boykow, George; Caplen, Mary Ann; Clemmons, Anthony; Compton, Douglas S; Hoos, Lizbeth; McGregor, Daniel G; Schnitzer-Polokoff, Robin; Smith, April A.; Weig, Blair; Zilli, D L; Clader, John W.; Sybertz, Edmund J.

doi:10.1016/0021-9150(94)05499-9

Cited by 105 publications

(74 citation statements)

References 38 publications

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“…Cholesterol, cholesteryl ester, and TG concentrations were determined by comparison to standard curves using Non-polar Lipid Mix-B, Matreya, Inc., Pleasant Gap, PA, USA, C/N 1130. The accumulation of hepatic free cholesterol (FC) and cholesteryl esters was used as a surrogate marker of cumulative cholesterol absorption and its inhibition in mice (Salisbury et al 1995). Data were reported as mg/g liver and mg/liver.…”

Section: Plasma and Hepatic Lipid Measurementsmentioning

confidence: 99%

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Vassileva

Hu²,

Hoos³

et al. 2010

Journal of Endocrinology

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G-protein-coupled bile acid receptor 1 (GPBAR1/TGR5/ M-Bar/GPR131) is a cell surface receptor involved in the regulation of bile acid metabolism. We have previously shown that Gpbar1-null mice are resistant to cholesterol gallstone disease when fed a lithogenic diet. Other published studies have suggested that Gpbar1 is involved in both energy homeostasis and glucose homeostasis. Here, we examine the functional role of Gpbar1 in diet-induced obese mice. We found that body weight, food intake, and fasted blood glucose levels were similar between Gpbar1-null mice and their wild-type (WT) littermates when fed a chow or high-fat diet (HFD) for 2 months. However, insulin tolerance tests revealed improved insulin sensitivity in male Gpbar1 K/K mice fed chow, but impaired insulin sensitivity when fed a HFD. In contrast, female Gpbar1 K/K mice exhibited improved insulin sensitivity when fed a HFD compared with their WT littermates. Female Gpbar1 K/K mice had significantly lower plasma cholesterol and triglyceride levels than their WT littermates on both diets. Male Gpbar1 K/K mice on HFD displayed increased hepatic steatosis when compared with Gpbar1 C/C males and Gpbar1 K/K females on HFD. These results suggest a gender-dependent regulation of Gpbar1 function in metabolic disease.

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Section: Plasma and Hepatic Lipid Measurementsmentioning

confidence: 99%

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Vassileva

Hu²,

Hoos³

et al. 2010

Journal of Endocrinology

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“…Hepatic cholesteryl ester (CE) accumulation, previously reported as an indicator of chronic intestinal cholesterol absorption status, 13 Table I). Reducing cholesterol absorption by ezetimibe or through lack of Npc1l1 prevents cholesterol diet-induced accumulation of hepatic cholesteryl esters.…”

Section: Hepatic and Biliary Cholesterol Determinationmentioning

confidence: 99%

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Davis¹,

Hoos²,

Tetzloff³

et al. 2007

ATVB

118

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Objective-The objective of this study was to determine whether the deficiency of Niemann-Pick C1 Like 1 (Npc1l1) prevents atherosclerosis in apoE null mice. Methods and Results-Npc1l1Ϫ/Ϫ /apoE null Ϫ/Ϫ mice were generated and found to have a significant reduction in cholesterol absorption (Ϫ77%) compared with wild-type or apoE Ϫ/Ϫ mice. Npc1l1/apoE Ϫ/Ϫ mice were fed a chow or Western diet for 24 weeks, then lipoprotein, hepatic, and biliary cholesterol, and atherosclerosis development was compared with apoE Ϫ/Ϫ , Npc1l1 Ϫ/Ϫ , wild-type, and ezetimibe-treated apoE Ϫ/Ϫ mice. Chylomicron remnant/ VLDL cholesterol levels were reduced 80% to 90% in both chow and Western diet-fed Npc1l1/apoE Ϫ/Ϫ mice relative to apoE Ϫ/Ϫ mice. Male Npc1l1 Ϫ/Ϫ and Npc1l1/apoE Ϫ/Ϫ mice were completely resistant to diet induced hypercholesterolemia, and both male and female mice were completely resistant to increases in hepatic and biliary cholesterol levels. Atherosclerosis was reduced 99% in aortic lesion surface area, 94% to 97% in innominate artery intimal lesion area, and Ͼ90% in aortic root lesion area in both male and female Npc1l1/apoE Ϫ/Ϫ mice relative to apoE Ϫ/Ϫ mice. Conclusions-Lack of Npc1l1, the molecular target of the cholesterol absorption inhibitor ezetimibe, in apoE Ϫ/Ϫ mice results in a significant reduction in cholesterol absorption and plasma cholesterol levels, and causes a nearly complete protection from the development of atherosclerosis, under both cholesterol-fed and non-cholesterol-fed conditions.

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“…to be a saturable process that is sensitive to protease treatment (Bhattacharyya and Connor, 1974); (b) potent saponins, such as pamaqueside, are effective in inhibiting cholesterol transport at concentrations below doses required to complex cholesterol in a 1:1 molar ratio, possibly by interfering directly with a putative cholesterol transporter molecule in the intestine (Salisbury et al, 1995;Morehouse et al, 1999); (c) the poor intestinal absorption of closely related plant sterol molecules suggests discrimination in absorption (Salen et al, 1970); (d) patients with sitosterolemia, a rare inherited disorder, lose the ability to discriminate between plant sterols and cholesterol, resulting in the accumulation of sistosterol in plasma and tissues (Bhattacharyya and Connor, 1974), and (e) the heterogeneity of cholesterol absorption efficiency in animal species and humans remains an enigma (Bhattacharyya and Eggen, 1980;Kushwaha et al, 1993;St Clair et al, 1981;Turley et al, 1997;Shwarz et al, 1998), which suggests a genetic component to the transport process.…”

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confidence: 99%

Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine

Lévy

Ménard

Suc

et al. 2004

Journal of Cell Science

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Studies employing human fetal intestine have yielded remarkable information on the role of polarized enterocytes in fat absorption. In this report, we investigated the intestinal expression, spatiotemporal distributions, ontogeny and function of the scavenger receptor, Class B, Type I (SR-BI) that plays a crucial role in cholesterol homeostasis. SR-BI was detected as early as week 14 of gestation in all gut segments and was almost entirely confined to the absorptive epithelial cells. By using immunofluorescence staining, the distribution of SR-BI rarely appeared as a gradient, increasing from the developing crypt to the tip of the villus. Western blot showed high levels of immunodetectable SR-BI in the duodenum, which progressively decreased toward the distal colon. The high-resolution immunogold technique revealed labelling mainly over microvilli of the enterocyte. SR-BI was not associated with caveolin-1 and was not detectable in caveolae. In order to define the role of SR-BI in intestinal cholesterol absorption, Caco-2 cells were transfected with a constitutive expression vector (pZeoSV) containing human SR-BI cDNA inserted in an antisense orientation. As noted by immunoblotting and Protein A-gold techniques, stable transformants contained 40, 60 and 80% the SR-BI level of control Caco-2 cells and exhibited a proportional drop in free cholesterol uptake without altering the capture of phospholipids or cholesteryl ester. Confirmation of these data was obtained in intestinal organ culture where SR-BI antibodies lowered cholesterol uptake. These observations suggest that the human intestine possesses a developmental and regional SR-BI pattern of distribution, and extends our knowledge in SR-BI-mediated cholesterol transport.

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Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461

Cited by 105 publications

References 38 publications

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice

Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine

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Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461

Cited by 105 publications

References 38 publications

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Gender-dependent effect of Gpbar1 genetic deletion on the metabolic profiles of diet-induced obese mice

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE −/− Mice

Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine

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Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE ^−/− Mice