Abstract
Despite numerous studies, the effects of ezetimibe on glucose metabolism are poorly understood. Here, we aimed to investigate the effects of ezetimibe on glucose metabolism and the expression of inflammatory markers. Thirteen rats were randomly assigned to an ezetimibe (n = 6) or control group (n = 7). The control group received a high fat diet (HFD; 60 Kcal%), whereas the ezetimibe group received an HFD (60 Kcal%) containing 160 mg/kg of ezetimibe. After 14 weeks, adipose and liver tissues, along with plasma, were collected and comparatively analyzed. The effects of combination therapy with ezetimibe and statins on glucose metabolism were investigated over a 1-year period using data from patients with hyperlipidemia. Several indices of glucose metabolism partially improved in the ezetimibe group. The sizes of adipocytes and the accumulation of pro-inflammatory cytokines were reduced in the ezetimibe group. Ezetimibe treatment induced anti-inflammatory cytokines and fatty acid oxidation in adipocytes and reduced serum levels of free fatty acids. Clinical data analysis revealed that statin monotherapy significantly increased insulin resistance. However, combination therapy with ezetimibe and statins did not increase insulin resistance. In conclusion, ezetimibe was found to reduce the sizes of adipocytes in visceral fat and serum levels of free fatty acids, to induce fatty acid oxidation, to improve adipocytic inflammation, and to partially improve glycemic index values.
Highlights
Ezetimibe is a hyperlipidemic drug that selectively inhibits cholesterol absorption by binding to the cholesterol carrier, Niemann-Pick C1 like 1 (NPC1L1), which is present in intestinal membranes.Ezetimibe lowers the serum levels of cholesterol by suppressing the absorption of intestinal cholesterol
We aimed to investigate the effects of ezetimibe on glucose metabolism both in vitro and in vivo by administering a high fat diet (HFD) to rats expressing hepatic NPC1L1, similar to humans
insulin tolerance test (ITT) revealed a significant reduction in blood glucose levels in the ezetimibe group at 30 and 60 min, compared to those in the control group (Supplementary Figure S1)
Summary
Ezetimibe is a hyperlipidemic drug that selectively inhibits cholesterol absorption by binding to the cholesterol carrier, Niemann-Pick C1 like 1 (NPC1L1), which is present in intestinal membranes. Ezetimibe lowers the serum levels of cholesterol by suppressing the absorption of intestinal cholesterol. It can be used as a supplementary or alternative drug when the hypolipidemic effects of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are insufficient or their usage is contraindicated. The expression of hepatic NPC1L1 is abundant in humans, but is very low in mice [14], and its role in glucose metabolism remains unclear. We aimed to investigate the effects of ezetimibe on glucose metabolism both in vitro and in vivo by administering a high fat diet (HFD) to rats expressing hepatic NPC1L1, similar to humans. By identifying the molecular mechanisms underlying the effects of ezetimibe, we aimed to determine whether ezetimibe therapy can be safely administered to patients with diabetes and hepatic steatosis
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