Potent Cholesterol Absorption Inhibitor Research Articles

On the population pharmacokinetics and the enterohepatic recirculation of total ezetimibe

Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC).The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance.Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake.The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation.

Synthesis and evaluation of 1H-pyrrole-2,5-dione derivatives as cholesterol absorption inhibitors for suppressing the formation of foam cells and inflammatory response

Excess lipid accumulation in the arterial intima and formation of macrophage-derived foam cells in the plaque could cause atherosclerotic lesion. Cholesterol absorption inhibitors could suppress the lipid accumulation of human macrophage, inflammatory response and the development of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized as cholesterol absorption inhibitor and tested in in vitro experiments. One of the most active inhibitors, compound 20 exhibited stronger in vitro cholesterol absorption activity than ezetimibe, no cytotoxicity in HEK293 and RAW264.7 cell lines and satisfied lipophilicity. The further study indicated that 20 could inhibit lipid accumulation of macrophage and reduce the secretion of LDH, MDA, TNF-α and ROS in a concentration-dependent manner. In conclusion, as a novel and potent cholesterol absorption inhibitor, compound 20 could suppress the formation of foam cells and inflammatory response.

Ezetimibe for the treatment of non-alcoholic fatty liver disease: A meta-analysis.

Several studies on the efficacy of ezetimibe, a potent inhibitor of cholesterol absorption, in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been published; however, the results are inconsistent. We undertook a meta-analysis to evaluate the efficacy of ezetimibe in treating NAFLD and NASH. PubMed, Medline, and Cochrane Library Full Text Database were searched until June 2016. The main inclusion criteria included original studies investigating the use of ezetimibe for the treatment of NAFLD and NASH. Identification of published work and data extraction were carried out by two reviewers based on the inclusion and exclusion criteria. All analyses were carried out using Comprehensive Meta-Analysis version 3 software. An initial search identified 103 peer-reviewed articles and abstracts. Six studies (two randomized controlled and four single-arm trials) involving 273 participants with NAFLD and NASH were identified. Ezetimibe significantly reduced serum aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transpeptidase levels, and hepatic steatosis and hepatocyte ballooning. However, hepatic inflammation and fibrosis did not improve by ezetimibe treatment in patients with NAFLD and NASH. In randomized controlled trials, only hepatocyte ballooning improved with ezetimibe treatment. Although ezetimibe attenuated serum liver enzymes and hepatic steatosis and ballooning in six studies, it improved only hepatocyte ballooning in randomized controlled trials. Larger studies and more randomized placebo-controlled trials are necessary to determine the effects of ezetimibe on NAFLD and NASH.

Discovery of 2-azetidinone and 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain as potential cholesterol absorption inhibitors.

Cholesterol absorption inhibitor (CAI) targeting Niemann-Pick C1-like1 protein was developed for the treatment of hyperlipidaemia and only ezetimibe was approved so far. For developing novel CAIs, we synthesized sixteen 2-azetidinone derivatives and thirteen 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain, and their inhibitory activity of cholesterol absorption was evaluated in Caco-2 cell line in vitro. Furthermore, top six compounds were measured by cytotoxicity and partition coefficient, and 2-azetidinone analogue 9e was selected for in vivo study. Finally, 9e considerably reduced total cholesterol, LDL-C, FFA and triglyceride in the serum and increased the rate of HDL-C to total cholesterol, suggesting it could regulate the lipid metabolism and act as a potent CAI.

Glucagon receptor antagonism induces increased cholesterol absorption

Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes mellitus (T2DM), plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor (GCGR) antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule GCGR antagonist (GRA), MK-0893, demonstrated dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose for 12 weeks in T2DM. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased glucagon-like peptide 2 and cholesterol absorption. There was not, however, a GRA-related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRAs. To examine potential pharmacologic mitigation, coadministration of ezetimibe (a potent inhibitor of cholesterol absorption) in mice abrogated the GRA-associated increase of LDL-c. Although the molecular mechanism is unknown, our results provide a novel finding by which glucagon and, hence, GCGR antagonism govern cholesterol metabolism.

Efficacy of ezetimibe is not related to NPC1L1 gene polymorphisms in a pilot study of Chilean hypercholesterolemic subjects.

Niemann-Pick C1 Like 1 (NPC1L1) is a multi-transmembrane transport protein highly expressed in the small intestine. It mediates sterol transfer throughout the brush border membrane of enterocytes, becoming essential for intestinal cholesterol absorption and ensuing whole-body cholesterol homeostasis. This protein is targeted by ezetimibe, a potent cholesterol absorption inhibitor. Single nucleotide polymorphisms (SNPs) in NPC1L1 have been associated to variation in both plasma low-density lipoprotein (LDL) cholesterol levels and lipid-lowering medication with ezetimibe. However, there are no data evaluating the impact of NPC1L1 variants on Chilean subjects medicated with ezetimibe monotherapy. Therefore, we assessed the contribution of two unexplored NPC1L1 variants on plasma lipids and response to ezetimibe in Chilean hypercholesterolemic individuals. Using PCR-restriction fragment length polymorphism (RFLP), we analyzed the SNP distribution of two common variants; -133A>G (rs17655652) and 1679C>G (rs2072183), and their relation with plasma lipids and lipid-lowering response to ezetimibe in 60 hypercholesterolemic Chilean subjects. Genotype distribution for the rs17655652 variant was AA 57 %, 40 % AG and 3 % GG, whereas for the rs2072183 SNP was 57 % CC, 35 % CG and 8 % GG. Minor allele frequencies (MAFs) were 0.23 and 0.26, respectively. No association was observed between NPC1L1 SNPs and baseline cholesterol. After therapy, none of the polymorphisms affected ezetimibe response in the studied cohort (P > 0.05). Data obtained indicates that polymorphisms rs17655652 and rs2072183 were not related to cholesterol variability. Also, lipid-lowering response to ezetimibe is not impacted by the NPC1L1 polymorphisms studied in Chilean hypercholesterolemic subjects.

Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice.

Oestrogen is an important risk factor for cholesterol cholelithiasis not only in women of childbearing age taking oral contraceptives and postmenopausal women undergoing hormone replacement therapy, but also in male patients receiving oestrogen therapy for prostatic cancer. In women, hormonal changes occurring during pregnancy markedly increase the risk of developing gallstones. We investigated whether the potent cholesterol absorption inhibitor ezetimibe could prevent the formation of oestrogen-induced cholesterol gallstones in mice. Following ovariectomy, female AKR mice were implanted subcutaneously with pellets releasing 17β-estradiol at 6μg/day and fed a lithogenic diet supplemented with ezetimibe in doses of 0 or 8mg/kg/day for 8weeks. Cholesterol crystallization and gallstone prevalence, lipid concentrations and composition in bile, and biliary lipid output were analysed by physical-chemical methods. Intestinal cholesterol absorption efficiency was determined by faecal dual-isotope ratio methods. Ezetimibe inhibited intestinal cholesterol absorption, while significantly reducing hepatic secretion of biliary cholesterol. Consequently, bile was desaturated through the formation of numerous unsaturated micelles and gallstones were prevented by ezetimibe in mice exposed to high doses of oestrogen and fed the lithogenic diet. Ezetimibe did not influence mRNA levels of the classical oestrogen receptors α (ERα) and ERβ, as well as a novel oestrogen receptor the G protein-coupled receptor 30 (GPR30) in the liver. Ezetimibe protects against the oestrogen-mediated lithogenic actions on gallstone formation in mice. Our finding may provide an efficacious novel strategy for the prevention of cholesterol gallstones in high-risk subjects, especially those exposed to high levels of oestrogen.

Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.

Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.

Ezetimibe markedly attenuates hepatic cholesterol accumulation and improves liver function in the lysosomal acid lipase-deficient mouse, a model for cholesteryl ester storage disease

Lysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wolman disease (WD) when the mutations cause complete loss of LAL activity. A rat model for WD and a mouse model for CESD have been described. In these studies we used LAL-deficient mice to investigate how modulating the amount of intestinally-derived cholesterol reaching the liver might impact its mass, cholesterol content, and function in this model. The main experiment tested if ezetimibe, a potent cholesterol absorption inhibitor, had any effect on CE accumulation in mice lacking LAL. In male Lal−/− mice given ezetimibe in their diet (20mg/day/kg bw) for 4weeks starting at 21days of age, both liver mass and hepatic cholesterol concentration (mg/g) were reduced to the extent that whole-liver cholesterol content (mg/organ) in the treated mice (74.3±3.4) was only 56% of that in those not given ezetimibe (133.5±6.7). There was also a marked improvement in plasma alanine aminotransferase (ALT) activity. Thus, minimizing cholesterol absorption has a favorable impact on the liver in CESD.

Physiological role of hepatic NPC1L1 in human cholesterol and lipoprotein metabolism: New perspectives and open questions

The importance of the cholesterol transporter Niemann-Pick C1 like protein 1 (NPC1L1)in the small intestine for efficient absorption of cholesterol is well documented and its physiological importance is clear (1). Similarly, the drug ezetimibe (Zetia™), which blocks function of this transporter, reduces plasma cholesterol, primarily LDL, by dramatically reducing intestinal absorption of dietary and biliary cholesterol (2). There are controversies about the exact mechanism by which NPC1L1 functions: whether the protein is on the apical cell membrane or intracellular vesicles or both (3–5), and whether ezetimibe directly blocks NPC1L1 or interrupts its association with other proteins in the sterol absorption and transport pathway (6–8). Nevertheless, it is now accepted that this protein is the key player in sterol absorption, although other transporters may play ancillary roles (9, 10).

Lipase catalyzed kinetic resolution for the production of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one: An intermediate for the synthesis of ezetimibe

Efficient enzymatic methods were developed for the synthesis of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one, by transesterification of (RS)-3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4(S)-4-phenyl-1,3-oxazolidin-2-one [(R,S)-FOP alcohol] and hydrolysis of (RS)-1-(4-fluorophenyl)-5-oxo-5-[(S)-2-oxo-4-phenyloxazolidin-3-yl] pentyl acetate [(R,S)-FOP acetate] using lipase as enzyme source. The synthesized S-diastereomer is an intermediate for the potent cholesterol absorption inhibitor, ezetimibe. Among various lipases tried, Candida rugosa lipase in diisopropyl ether was best for both the reactions. Vinyl acetate was found as suitable acyl donor in transesterification reaction. A higher amount of enzyme (500 mg) was required for the transesterification of 10 mM substrate; it may be due to the enzyme denaturation by acetaldehyde formed in the reaction. The ester hydrolysis reaction worked well, excellent conversion and de were obtained at 40 °C, pH 7. The 300 mg enzyme hydrolyzed 120 mg (R,S)-FOP acetate with 50% conversion and 99.5% de.

Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann–Pick C1-Like 1 only in liver

Niemann-Pick C1-Like 1 (NPC1L1) is highly expressed in the small intestine across mammalian species and is the target of ezetimibe, a potent cholesterol absorption inhibitor. In humans, NPC1L1 is also expressed in the liver. We found that transgenic overexpression of NPC1L1 in the wild-type mouse liver inhibits biliary cholesterol secretion and raises blood cholesterol, which can be reversed by ezetimibe treatment. Unfortunately, the high expression of endogenous NPC1L1 in the intestine hampered a definitive establishment of the role of hepatic NPC1L1 in cholesterol metabolism and ezetimibe action in the liver because intestinal NPC1L1 dramatically influences cholesterol homeostasis and is a target of ezetimibe. To circumvent this obstacle, we crossed liver-specific NPC1L1 transgenic mice to NPC1L1 knockout (L1-KO) mice and created a mouse line expressing no endogenous NPC1L1, but human NPC1L1 in liver only (L1 LivOnly mice). Compared to L1-KO mice, L1 LivOnly mice on a 0.2% cholesterol diet showed significantly increased hepatic and plasma cholesterol, and despite a 90% reduction in biliary cholesterol excretion, their fecal cholesterol excretion remained completely unaltered. Remarkably, 4 days of ezetimibe treatment significantly restored biliary cholesterol secretion in L1 LivOnly mice. These findings demonstrated a direct role of hepatic NPC1L1 in regulating biliary cholesterol excretion and hepatic/blood cholesterol levels, and unequivocally established hepatic NPC1L1 as a target of ezetimibe.

The ezetimibe controversy: implications for clinical practice

Low-density lipoprotein cholesterol (LDL-C) remains the primary target of lipid-lowering therapy. Achieving LDL-C goals as outlined by the National Cholesterol Education Program Adult Treatment Panel III can be difficult with statins alone; therefore, adjunctive therapy is often indicated to reduce cardiovascular risk. Ezetimibe, a potent inhibitor of intestinal cholesterol absorption, has been shown to be safe, tolerable and effective at lowering LDL-C, non-high-density lipoprotein cholesterol and apolipoprotein B, each of which has been correlated with improved clinical outcomes, alone or in combination with a statin. However, because of randomized trials that demonstrated mixed results about atherosclerotic plaque regression via carotid intima-media thickness and a concern about cancer risk, ezetimibe's role in lipid therapy has been questioned. Currently, a large randomized controlled trial is in progress to answer if ezetimibe improves clinical outcomes in patients with high-risk acute coronary syndrome. A smaller trial in patients with chronic kidney disease demonstrated reduced clinical events, including myocardial infarction, stroke and revascularization for patients taking the combination of ezetimibe and simvastatin versus those taking statin or placebo alone. In this paper, we review the trials that have led to the ezetimibe controversy and then discuss the possible role of ezetimibe in specific patient populations until the results of ongoing clinical trials are known.

Niemann-Pick C1-Like 1 (NPC1L1) Protein in Intestinal and Hepatic Cholesterol Transport

Increased blood cholesterol is an independent risk factor for atherosclerotic cardiovascular disease. Cholesterol homeostasis in the body is controlled mainly by endogenous synthesis, intestinal absorption, and hepatic excretion. Niemann-Pick C1-Like 1 (NPC1L1) is a polytopic transmembrane protein localized at the apical membrane of enterocytes and the canalicular membrane of hepatocytes. It functions as a sterol transporter to mediate intestinal cholesterol absorption and counter-balances hepatobiliary cholesterol excretion. NPC1L1 is the molecular target of ezetimibe, a potent cholesterol absorption inhibitor that is widely used in treating hypercholesterolemia. Recent findings suggest that NPC1L1 deficiency or ezetimibe treatment also prevents diet-induced hepatic steatosis and obesity in addition to reducing blood cholesterol. Future studies should focus on molecular mechanisms underlying NPC1L1-dependent cholesterol transport and elucidation of how a cholesterol transporter modulates the pathogenesis of metabolic diseases.

Ezetimibe and Reactive Oxygen Species

Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia. Statin, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is an inhibitor of cholesterol synthesis. Statin is the first-choice drug to reduce low-density lipoprotein (LDL)-cholesterol for patients with hypercholesterolemia, due to its strong effect to lower the circulating LDL-cholesterol levels. Because a high dose of statins causes concern about rhabdomyolysis, it is sometimes difficult to achieve the guideline-recommended levels of LDL-cholesterol in patients with high LDL-cholesterol treated with statin monotherapy. Ezetimibe has been reported to reduce LDL-cholesterol safely with both monotherapy and combination therapy with statins. Ezetimibe is especially expected to be the best pharmacological option for the treatment of patients unable to achieve LDL-cholesterol goals with statins. Reactive oxygen species (ROS) are produced at low levels to maintain physiological redox balance. Oxidative stress results when ROS production exceeds the ability of cells to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Oxidative stress exacerbates atherosclerosis, the major risk factor for coronary artery disease and ischemic stroke, at every step involves the accumulation of oxidized LDL in the arteries, leading to foam cell formation, plaque development, and plaque rupture. This review focuses on the recent findings of ezetimibe-related atheroprotective effects in vasculature. Moreover, known and proposed mechanisms of how ezetimibe could improve ROS-induced pro-atherosclerotic conditions in vasculature are discussed; these effects may help to explain the mechanisms by which ezetimibe may protect vascular from atherosclerosis.

Induction of microsomal triglyceride transfer protein expression is a candidate mechanism by which ezetimibe therapy might exert beneficial effects in patients with nonalcoholic steatohepatitis

Dear Editor Park and colleagues have reported that ezetimibe therapy improves the histological abnormalities of nonalcoholic fatty liver disease (NAFLD) [1]. In their study, while no significant difference was observed in the fibrosis stage, significant improvements of the steatosis grade, necroinflammatory grade, ballooning score, and NAFLD activity score (NAS) were observed after treatment with ezetimibe (10 mg/day) for 24 months. Ezetimibe, a potent inhibitor of cholesterol absorption, has been shown to inhibit Niemann-Pick C1 Like 1 (NPC1L1)-dependent cholesterol transport at the brush border of the intestine and the liver [2]. Therefore, ezetimibe has been considered as a noteworthy candidate agent for the treatment of metabolic syndrome, including nonalcoholic steatohepatitis (NASH). In several experimental rodent models, drugs antagonizing mechanisms such as sterol regulatory element-binding protein-1c (SREBP-1c) induction, carbohydrate responsive binding protein (ChREBP) induction, and endoplasmic reticulum (ER) stress have been reported as candidate mechanisms for the improvement of hepatic steatosis [3, 4]. However, unlike in rodents, in which NPC1L1 is mainly expressed in the intestine, in humans high levels of expression of NPC1L1 mRNA are observed in both the small intestine and the liver; therefore, ezetimibe would inhibit not only dietary and biliary cholesterol absorption in the small intestine, but also biliary cholesterol absorption in the liver [2]. Therefore, the mechanism by which ezetimibe might improve the changes of NASH in humans remains unknown. We conducted a 6-month pilot study to investigate the effect of ezetimibe in patients with NASH [5]. To investigate the mechanism of action of ezetimibe treatment in human NASH patients, we analyzed the hepatic mRNA expression of SREBP1c, ChREBP, and ER stress in 8 NASH patients before and after ezetimibe treatment. We found no significant changes in SREBP1c expression, ChREBP expression, or ER stress (Glucose-regulated protein 78, C/EBP-homologous protein) in this study. Secondly, we examined microsomal triglyceride transfer protein (MTTP) expression, which is a key factor for triglyceride (TG) transport in the liver, because we had previously found that the hepatic expression of MTTP mRNA was impaired in NASH patients as compared with that in patients with simple steatosis [6]. After ezetimibe treatment, a significant increase of hepatic MTTP mRNA expression was observed as compared with that before ezetimibe treatment (p = 0.0052). We suggest, therefore, that the induction of MTTP expression is an important candidate mechanism by which ezetimibe therapy might exert beneficial effects against NAFLD in humans.

Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption. NPC1L1 knockout (L1-KO) mice were recently shown to be resistant to high-fat diet (HFD)-induced obesity in one study, which was contrary to several other studies. Careful comparison of dietary compositions in these studies implies a potential role of dietary cholesterol in regulating weight gain. To examine this potential, wild-type (WT) and L1-KO mice were fed one of three sets of diets for various durations: (1) a HFD without added cholesterol for 5 weeks; (2) a high-carbohydrate diet with or without added cholesterol for 5 weeks; or (3) a synthetic HFD with or without added cholesterol for 18 weeks. We found that L1-KO mice were protected against diet-induced weight gain only on a diet without added cholesterol but not on a diet containing 0.16% or 0.2% (w/w) cholesterol, an amount similar to a typical Western diet, regardless of the major energy source of the diet. Food intake and intestinal fat absorption were similar between the two genotypes. Intestinal cholesterol absorption was blocked, and fecal cholesterol excretion increased in L1-KO mice. Under all diets, L1-KO mice were protected from hepatosteatosis. In conclusion, increasing dietary cholesterol restores diet-induced weight gain in mice deficient in NPC1L1-dependent cholesterol absorption.

Effect of ezetimibe on incretin secretion in response to the intestinal absorption of a mixed meal.

Ezetimibe is a potent inhibitor of cholesterol absorption by enterocytes. Although ezetimibe minimally affects the absorption of triglyceride, it is unknown whether ezetimibe affects the secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). It has been shown that ezetimibe-treated mice are protected from diet-induced insulin resistance. Since GIP and GLP-1 promote the actions of insulin, we hypothesized that ezetimibe may affect the secretion of GIP and GLP-1 by enteroendocrine cells into lymph in response to the intestinal absorption of a mixed meal (Ensure). To test this hypothesis, we used the lymph fistula rat model to determine GIP and GLP-1 concentrations in lymph during the 2 h after the infusion of Ensure. Ezetimibe significantly reduced lymphatic cholesterol output during fasting, without coincident decreases in glucose, protein, and triglyceride outputs. However, ezetimibe did not influence cholesterol output after infusion of Ensure. Interestingly, ezetimibe significantly reduced the secretion of both GIP and GLP-1 into lymph after the infusion of Ensure. Therefore, the inhibitory effect of ezetimibe on GIP and GLP-1 secretion by enteroendocrine cells occurs outside of the effects of glucose, protein, or triglyceride secretion by the intestine.

Effect of ezetimibe on the response of incretin secretion to intestine lipid ingestion

BackgroundEzetimibe (EZ) is a potent inhibitor of cholesterol absorption by enterocytes. Although EZ minimally affects fat absorption, it is unknown if EZ affects the secretion of incretins glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) during triglyceride (TG) absorption.AimWe determined if EZ influences the lymphatic secretion of incretins stimulated by the ingestion of Ensure.MethodsIn SD rats, the mesenteric lymph duct was cannulated and a duodenal infusion tube was installed. EZ (0.67 mg/kg) or saline was infused duodenally 2 h prior to the feeding of a 3 ml bolus dose of Ensure (4.43 kcal). To determine glucose, TG, cholesterol, GIP, and GLP‐1 concentrations, lymph samples were collected 2 h before and 2 h after infusion of Ensure.ResultsEZ did not affect lymph flow, glucose or TG output stimulated by Ensure compared with the control rats. As expected, EZ did significantly reduce lymphatic cholesterol output. Interestingly, EZ significantly reduced the stimulation of lymphatic secretion of GIP and GLP‐1 induced by Ensure.ConclusionsReduced secretion of GIP and GLP‐1 by the enteroendocrine cells is associated with decreased cholesterol secretion in EZ‐treated rats. Moreover, this response of intestinal incretin secretion is independent from the uptake of dietary TG. The mechanism involved remains to be elucidated. This work was supported by NIH.

Transporters as Drug Targets: Discovery and Development of NPC1L1 Inhibitors

The potent cholesterol absorption inhibitor ezetimibe was developed as a first-in-class drug for treating hypercholesterolemia even before its molecular target, Niemann-Pick C1-like 1 (NPC1L1), had been identified. The NPC1L1 protein mediates sterol transport across the enterocyte brush border membrane and is essential for intestinal cholesterol absorption, a major pathway controlling whole-body cholesterol homeostasis. An elucidation of the mechanism underlying NPC1L1-dependent cholesterol absorption would greatly facilitate the discovery and development of new cholesterol-lowering agents for treating hypercholesterolemia and other cholesterol-related metabolic disorders.