Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and<i>Npc1l1</i><sup>−/−</sup>mice

Labonté, Eric D.; Camarota, Lisa M.; Rojas, Juan C.; Jandacek, Ronald J.; Gilham, Dean; Davies, Joanna P.; Ioannou, Yiannis A.; Tso, Patrick; Hui, David Y.; Howles, Philip N.

doi:10.1152/ajpgi.90275.2008

Cited by 106 publications

(108 citation statements)

References 56 publications

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“…A postprandial increase in the TG level induces an increase in free fatty acid (FFA), which is known to induce insulin resistance by inhibiting the binding of insulin to the insulin receptor. Recently, ezetimibe was reported to inhibit the absorption of FFA by downregulation of fatty acid transfer protein-4 29,30) . Ezetimibe is also thought to inhibit postprandial chylomicron secretion 31) , and this effect secondarily causes a reduction in TG transport to the liver as well as reduced serum FFA levels.…”

Section: Discussionmentioning

confidence: 99%

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Tamaki

Ueno

Morinaga

et al. 2012

JAT

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Aim: Ezetimibe reduces serum low-density lipoprotein cholesterol (LDL-C) levels by inhibiting intestinal cholesterol absorption; however, the effects of ezetimibe, including its pleiotropic effects, have not been fully clarified. The aims of our study were to examine the efficacy of ezetimibe for hypercholesterolemia and its pleiotropic effects. Methods: Outpatients with hyper LDL-C levels were treated with 10 mg ezetimibe once a day for 12 weeks. Serum lipid profiles, atherosclerotic and inflammatory markers, glucose, insulin, liver function, and cholesterol absorption and synthesis markers were measured before and after treatment. Results: Seventy-five patients treated with ezetimibe monotherapy and 16 patients treated with combined therapy of ezetimibe with different statins completed this study. Following 12 weeks of ezetimibe monotherapy, serum LDL-C, triglyceride, remnant-like particles cholesterol, matrix metalloproteinase-9, insulin, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, the relative mobility of the peak of the LDL fraction, and cholesterol absorption markers were significantly decreased, and high-density lipoprotein cholesterol and lathosterol were significantly increased. In the combined therapy group, LDL-C and cholesterol absorption markers were significantly decreased after treatment. In patients with a high basal ALT level that were treated with monotherapy, ALT and the AST/ALT ratio were significantly decreased and increased, respectively, after treatment. Conclusion: Ezetimibe ameliorated not only atherogenic lipid profiles but also atherosclerotic and inflammatory markers, insulin sensitivity, and liver dysfunction in Japanese hypercholesterolemia patients, suggesting that ezetimibe treatment is a beneficial and effective strategy for the treatment of hypercholesterolemia, especially patients with obesity, metabolic syndrome, and/or fatty liver.

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Section: Discussionmentioning

confidence: 99%

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Tamaki

Ueno

Morinaga

et al. 2012

JAT

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“…In addition, ezetimibe has been reported to reduce postprandial hypertriglyceridaemia and inflammation and to improve insulin sensitivity 15,16) . In animals experiments, ezetimibe reversed dietinduced obesity 17,18) , liver steatosis [17][18][19][20] , and insulin resistance 19) . In humans, in addition to the effect of ezetimibe on lowering serum LDL-C 13) , its potential effects on liver steatosis 21) and insulin resistance 22) have been reported.…”

Section: Measurement Of Serum Samplesmentioning

confidence: 96%

Double-Blind Randomized Clinical Trial of the Effects of Ezetimibe on Postprandial Hyperlipidaemia and Hyperglycaemia

Kikuchi

Nezu

Inazumi

et al. 2012

JAT

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Aim: Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 (NPC1L1) and reducing LDL cholesterol (LDL-C). In animals, ezetimibe reversed dietinduced obesity, liver steatosis, and insulin resistance. In humans, its potential effects on liver steatosis and insulin resistance have been suggested. We investigated the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind randomized crossover trial. Methods: Twenty obese men with hypertriglyceridaemia were assigned randomly to an ezetimibe-or a placebo-precedence-treated group. Subjects in the ezetimibe group were treated with ezetimibe (10 mg/day) for the first 4 weeks, followed by a 4-week interval and then treated with placebo for another 4 weeks. The placebo group received these treatments in reverse order. Subjects were requested to fast for at least 12 hours and then received a standard meal. Blood samples were collected at 0, 30, 60, 120, 240, 360 and 480 minutes after the meal on Days 0, 28, 56 and 84 and were used to measure the lipid and glucose metabolism markers. Results: Ezetimibe significantly decreased the postprandial serum triglyceride excursion (p=0.01) and fasting serum LDL-C, remnant-like particles(RLP) and ApoB48 levels (p＜0.05). Postprandial glucose excursion, serum insulin levels, serum glucose-dependent insulinotropic polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) were not significantly affected by ezetimibe treatment. Conclusion: Ezetimibe restored the postprandial dysregulation of lipid but did not affect glucose metabolism in a double-blind randomized crossover trial.

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“…Administration of ezetimibe in humans, at a dose of 10 mg/ day, decreased absorption of cholesterol in the intestine by 54% compared with the placebo. The levels of plasma LDL-C was also reduced by 20% with an 89% compensatory rise in cholesterol biosynthesis in hepatic cells (35). On the other hand, use of garlic may play a vital role in the management of diabetes and CVD.…”

Section: Discussionmentioning

confidence: 99%

Combination of Ezetimibe and Garlic Reduces Serum Lipids and Intestinal Niemann-Pick C1-like 1 Expression More Effectively in Hypercholesterolemic Mice

Mohammadi¹,

Vafaei²,

Moradi³

et al. 2015

Avicenna J Med Biochem

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Background: Combination therapy plays an important role in the management of cardiovascular disease (CVD).Objectives: The aim of this experiment was to study the influence of garlic combined with ezetimibe on lipid profile as well as intestinal Niemann-Pick C1-like 1 (NPC1L1) expression in normal and hypercholesterolemic mice. Materials and Methods: A total of 40 mice were randomly divided into five groups: Group 1: hypercholesterolemic group (received 2% w/w cholesterol + 0.5% w/w cholic acid in their diet), Group 2: garlic group (hypercholesterolemic diet + 4% w/w garlic extract), Group 3: ezetimibe group (hypercholesterolemic diet + 0.005% w/w ezetimibe), Group 4: combination group (hypercholesterolemic diet + 0.005% w/w ezetimibe + 4% w/w garlic) and Group 5: control (chow only). Results: Serum low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) levels were significantly decreased in ezetimibe, garlic (both P < 0.05), and combination groups (P < 0.001). Also, triglycerides and very low-density lipoprotein-cholesterol (VLDL-C) were significantly lower in garlic and combination groups (P < 0.05). Liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were also significantly decreased in garlic, ezetimibe (both P < 0.05) and combination groups (P < 0.001) in comparison with hypercholesterolemic animals. Analysis of semi quantitative RT-PCR results showed that the levels of NPC1L1 was also significantly less (P < 0.01) in the garlic, ezetimibe, and combination groups (P < 0.001) compared with the controls. Based on the results, the combination of garlic and ezetimibe can lower serum lipids and liver enzymes more effectively in hypercholesterolemic mice. Conclusions: This experiment revealed that a possible mechanism for the beneficial effects of garlic and ezetimibe combination in lowering plasma LDL-C and TC is inhibition of intestinal cholesterol absorption. More research might be necessary to determine the efficacy and the exact mechanism of this co-administration.

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Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated andNpc1l1^−/−mice

Cited by 106 publications

References 56 publications

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Double-Blind Randomized Clinical Trial of the Effects of Ezetimibe on Postprandial Hyperlipidaemia and Hyperglycaemia

Combination of Ezetimibe and Garlic Reduces Serum Lipids and Intestinal Niemann-Pick C1-like 1 Expression More Effectively in Hypercholesterolemic Mice

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Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated andNpc1l1−/−mice

Cited by 106 publications

References 56 publications

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Ezetimibe Ameliorates Atherosclerotic and Inflammatory Markers, Atherogenic Lipid Profiles, Insulin Sensitivity, and Liver Dysfunction in Japanese Patients with Hypercholesterolemia

Double-Blind Randomized Clinical Trial of the Effects of Ezetimibe on Postprandial Hyperlipidaemia and Hyperglycaemia

Combination of Ezetimibe and Garlic Reduces Serum Lipids and Intestinal Niemann-Pick C1-like 1 Expression More Effectively in Hypercholesterolemic Mice

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Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated andNpc1l1^−/−mice