Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome

Deushi, Michiyo; Nomura, Mitsunori; Kawakami, Akio; Haraguchi, Mihoko; Ito, Mizuho; Okazaki, Mitsuyo; Ishii, Hiroko; Yoshida, Masayuki

doi:10.1016/j.febslet.2007.11.023

Cited by 150 publications

(142 citation statements)

References 34 publications

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“…Ezetimibe administration may be a favourable option for the treatment of patients with elevated VLDL, LDL and RLP-C levels. Several studies have shown that ezetimibe improved lipid metabolism in obese patients with dyslipidaemia and in animal models of metabolic syndrome 17,22,30) . Moreover, ezetimibe reportedly inhibits the elevation of hs-CRP 31) and improves endothelium-dependent acetylcholineinduced vasodilatation in patients with metabolic syndrome 32) , although we were unable to confirm these effects in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…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: 99%

“…These results suggested that glucose tolerance was not exacerbated by ezetimibe. Several studies in humans 16,17,26) showed that HbA1c was decreased by ezetimibe. The results of our animal study 25) supported the concept that ezetimibe ameliorates hepatic insulin resistance as well as dyslipidaemia and hepatic steatosis in high-fat dietinduced obese subjects.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Measurement Of Serum Samplesmentioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

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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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“…Liver disease Ezetimibe reduced histological ballooning and fibrosis in one RCT, and MR-assessed liver fat in the other [62,63] (ESM Table 3). …”

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confidence: 99%

Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

et al. 2012

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Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liverrelated complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardiometabolic risk in NAFLD. Methods Publications through November 2011 were systematically reviewed by two authors. Outcomes evaluated though standard methods were: histological/radiological/biochemical features of NAFLD, variables of glucose metabolism and cardiovascular risk factors. Seventy-eight randomised trials were included (38 in NASH, 40 in NAFLD): 41% assessed post-treatment histology, 71% assessed glucose metabolism and 88% assessed cardiovascular risk factors. Lifestyle intervention, thiazolidinediones, metformin and antioxidants were most extensively evaluated. Results Lifestyle-induced weight loss was safe and improved cardio-metabolic risk profile; a weight loss ≥7% improved histological disease activity, but was achieved by <50%

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“…This suggests that ezetimibe ameliorates toxic-lipid-induced inflammation and insulin resistance by inhibiting cholesterol absorption. Indeed, ezetimibe improves liver steatosis and insulin resistance in mice [7] and Zucker obese fatty rats [8], although the beneficial effects of ezetimibe are observed only when the animals are fed a high-fat diet. Ezetimibe can also ameliorate liver pathology in patients with NAFLD [9,10]; however, these studies lack a control group, which precludes meaningful conclusions as liver pathology can improve over the natural course of the disease or with tight glycaemic control in some NAFLD patients [1].…”

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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Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome

Cited by 150 publications

References 34 publications

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

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

Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

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

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