Ezetimibe

Ezetimibe is a potent and novel inhibitor of cholesterol absorption [1].

Cholesterol is a lipid molecule and is required to build and maintain membranes structural integrity and fluidity. Also, it serves as a precursor of vitamin D, bile acids and steroid hormones.

In differentiated Caco-2 cells incubated with a carotenoid (1 μM), ezetimibe (10 mg/L) inhibited carotenoid transport with 50% inhibition for ɑ-carotene and β-carotene. Also, it inhibited the transport of β-cryptoxanthin, lycopene and lutein:zeaxanthin(1:1). At the same time, ezetimibe inhibited cholesterol transport by 31%. Ezetimibe decreased the expression of the surface receptors SR-BI, ATP binding cassette transporter, subfamily A (ABCA1), Niemann-Pick type C1 Like 1 protein (NPC1L1) and retinoid acid receptor (RAR)γ, sterol-regulatory element binding proteins SREBP-1 and SREBP-2, and liver X receptor (LXR)β [3].

In apolipoprotein E knockout (apoE-/-) mice, ezetimibe (3 mg/kg) inhibited cholesterol absorption by 90%. Ezetimibe reduced plasma cholesterol, increased HDL levels, and inhibits the progression of atherosclerosis [1]. In phase III human trials, Ezetimibe (10 mg) significantly reduced the levels of LDL cholesterol, total cholesterol and triglycerides and increased the level of HDL cholesterol [2].

References:
[1].  Davis HR Jr, Compton DS, Hoos L, et al. Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice. Arterioscler Thromb Vasc Biol, 2001, 21(12): 2032-2038.
[2].  Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem, 2004, 47(1): 1-9.
[3].  During A, Dawson HD, Harrison EH. Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J Nutr, 2005, 135(10): 2305-2312.

Ezetimibe stimulates intestinal glucagon-like peptide 1 secretion via the MEK/ERK pathway rather than dipeptidyl peptidase 4 inhibition.[Pubmed:25704082]

Metabolism. 2015 May;64(5):633-41.

OBJECTIVE: Ezetimibe is known as a Niemann-Pick C1-Like 1 (NPC1L1) inhibitor and has been used as an agent for hypercholesterolemia. In our previous study, Ezetimibe administration improved glycemic control and increased glucagon like peptide-1 (GLP-1), an incretin hormone with anti-diabetic properties. However, the mechanisms by which Ezetimibe stimulates GLP-1 secretion are not fully understood. Thus, the specific aim of this study was to investigate the mechanism(s) by which Ezetimibe stimulates GLP-1 secretion. MATERIALS/METHODS: Male KK/H1J mice were divided into following groups: AIN-93G (NC), NC with Ezetimibe (10 mg/kg/day), 45% high fat (HF) diet, and HF diet with Ezetimibe. To investigate the role of Ezetimibe in glucose homeostasis and GLP-1 secretion, an insulin tolerance test was performed and serum and intestinal GLP-1 levels and intestinal mRNA expression involved in GLP-1 synthesis were measured after 6 weeks of Ezetimibe treatment. In vivo and in vitro dipeptidyl peptidase-4 (DPP-4) inhibition assays were employed to demonstrate the association between Ezetimibe-induced GLP-1 change and DPP-4. The molecular mechanism by which Ezetimibe affects GLP-1 secretion was evaluated by using human enteroendocrine NCI-H716 cells. RESULTS: Ezetimibe supplementation significantly ameliorated HF-increased glucose and insulin resistance in the type 2 diabetic KK/H1J mouse model. Serum and intestinal active GLP-1 levels were significantly increased by Ezetimibe in HF-fed animals. However, mRNA expression of genes involved in intestinal GLP-1 synthesis was not altered. Furthermore, Ezetimibe did not inhibit the activity of either in vivo or in vitro dipeptidyl peptidase-4 (DPP-4). The direct effects of Ezetimibe on GLP-1 secretion and L cell secretory mechanisms were examined in human NCI-H716 intestinal cells. Ezetimibe significantly stimulated active GLP-1 secretion, which was accompanied by the activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). Ezetimibe-increased GLP-1 secretion was abrogated by inhibiting the MEK/ERK pathway with PD98059. CONCLUSION: These findings suggest a possible novel biological role of Ezetimibe in glycemic control to stimulate intestinal GLP-1 secretion via the MEK/ERK signaling pathway.

Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial).[Pubmed:25482832]

Hepatology. 2015 Apr;61(4):1239-50.

UNLABELLED: Ezetimibe inhibits intestinal cholesterol absorption and lowers low-density lipoprotein cholesterol. Uncontrolled studies have suggested that it reduces liver fat as estimated by ultrasound in nonalcoholic steatohepatitis (NASH). Therefore, we aimed to examine the efficacy of Ezetimibe versus placebo in reducing liver fat by the magnetic resonance imaging-derived proton density-fat fraction (MRI-PDFF) and liver histology in patients with biopsy-proven NASH. In this randomized, double-blind, placebo-controlled trial, 50 patients with biopsy-proven NASH were randomized to either Ezetimibe 10 mg orally daily or placebo for 24 weeks. The primary outcome was a change in liver fat as measured by MRI-PDFF in colocalized regions of interest within each of the nine liver segments. Novel assessment by two-dimensional and three-dimensional magnetic resonance elastography was also performed. Ezetimibe was not significantly better than placebo at reducing liver fat as measured by MRI-PDFF (mean difference between the Ezetimibe and placebo arms -1.3%, P = 0.4). Compared to baseline, however, end-of-treatment MRI-PDFF was significantly lower in the Ezetimibe arm (15%-11.6%, P < 0.016) but not in the placebo arm (18.5%-16.4%, P = 0.15). There were no significant differences in histologic response rates, serum alanine aminotransferase and aspartate aminotransferase levels, or longitudinal changes in two-dimensional and three-dimensional magnetic resonance elastography-derived liver stiffness between the Ezetimibe and placebo arms. Compared to histologic nonresponders (25/35), histologic responders (10/35) had a significantly greater reduction in MRI-PDFF (-4.35 +/- 4.9% versus -0.30 +/- 4.1%, P < 0.019). CONCLUSIONS: Ezetimibe did not significantly reduce liver fat in NASH. This trial demonstrates the application of colocalization of MRI-PDFF-derived fat maps and magnetic resonance elastography-derived stiffness maps of the liver before and after treatment to noninvasively assess treatment response in NASH.

The effect of ezetimibe on androgen production in hypercholesterolemic women with polycystic ovary syndrome.[Pubmed:25056604]

Cardiovasc Ther. 2014 Oct;32(5):219-23.

AIMS: Statin therapy was found to reduce circulating androgen levels in patients with polycystic ovary syndrome (PCOS). No similar data are available for Ezetimibe. METHODS: The study included 14 women with PCOS and hypercholesterolemia, intolerant to statins or having contraindications to this treatment, who were treated with Ezetimibe (10 mg daily). They were compared with 14 matched women with both of these disorders receiving simvastatin (40 mg daily). Plasma lipids, glucose homeostasis markers, and serum levels of androgens, sex hormone-binding globulin, and gonadotropins were assessed at baseline and after 3 months of treatment. RESULTS: Both simvastatin and Ezetimibe decreased plasma levels of total and LDL cholesterol. Ezetimibe, but not simvastatin, slightly reduced insulin resistance. Simvastatin decreased serum levels of total testosterone (-23%, P < 0.001), free testosterone (-32%, P < 0.001), androstendione (-20%, P < 0.01), and dehydroepiandrosterone sulfate (-17%, P < 0.05), as well as tended to reduce the luteinizing hormone/follicle-stimulating hormone ratio (-23%, P = 0.095). Ezetimibe only insignificantly reduced serum levels of free testosterone (-14%, P = 0.098). There were no differences in the effects of simvastatin on circulating hormone levels between insulin-resistant and insulin-sensitive subjects. In turn, the effect of Ezetimibe on free testosterone levels was stronger in insulin-resistant patients. CONCLUSIONS: Although Ezetimibe and simvastatin are equipotent in lowering lipid levels in hypercholesterolemic patients with coexisting PCOS, simvastatin exhibits a more pronounced effect on circulating androgen levels in this group of patients.

Ezetimibe (SCH 58235) is a potent cholesterol absorption inhibitor. Ezetimibe is a Niemann-Pick C1-like1 (NPC1L1) inhibitor, and is a potent Nrf2 activator.

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