In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs

Hawes, Brian E.; O’Neill, Kim; Yao, Xiangdong; Crona, James H.; Davis, Harry R.; Graziano, Michael P.; Altmann, Scott

doi:10.1124/mol.106.027896

Cited by 59 publications

(52 citation statements)

References 36 publications

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“…It has been shown that both ezetimibe and its glucuronide metabolite inhibit cholesterol absorption but that the glucuronide derivative is more potent. This is likely related to the enhanced binding affinity of the glucuronide metabolite to NPC1L1 (4,8,(27)(28)(29). Thus, our observations with the parent drug may underestimate the effects of the glucuronyl metabolite.…”

Section: Discussionmentioning

confidence: 89%

Ezetimibe interferes with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum in CaCo-2 cells

Field

Watt

Mathur

2007

Journal of Lipid Research

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Niemann-Pick C1-like 1 protein (NPC1L1) is the putative intestinal sterol transporter and the molecular target of ezetimibe, a potent inhibitor of cholesterol absorption. To address the role of NPC1L1 in cholesterol trafficking in intestine, the regulation of cholesterol trafficking by ezetimibe was studied in the human intestinal cell line, CaCo-2. Ezetimibe caused only a modest decrease in the uptake of micellar cholesterol, but markedly prevented its esterification. Cholesterol trafficking from the plasma membrane to the endoplasmic reticulum was profoundly disrupted by ezetimibe without altering the trafficking of cholesterol from the endoplasmic reticulum to the plasma membrane. Cholesterol oxidase-accessible cholesterol at the apical membrane was increased by ezetimibe. Cholesterol synthesis was modestly increased. Although the amount of cholesteryl esters secreted at the basolateral membrane was markedly decreased by ezetimibe, the transport of lipids and the number of lipoprotein particles secreted were not altered. NPC1L1 gene and protein expression were decreased by sterol influx, whereas cholesterol depletion enhanced NPC1L1 gene and protein expression. These results suggest that NPC1L1 plays a role in cholesterol uptake and cholesterol trafficking from the plasma membrane to the endoplasmic reticulum. Interfering with its function will profoundly decrease the amount of cholesterol transported into lymph.-Field, F. J., K. Watt, and S. N. Mathur. Ezetimibe interferes with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum in CaCo-2 cells.

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Section: Discussionmentioning

confidence: 89%

Ezetimibe interferes with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum in CaCo-2 cells

Field

Watt

Mathur

2007

Journal of Lipid Research

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“…Atorvastatin inhibits hepatic cholesterol synthesis by inhibiting HMG-CoA reductase, whereas ezetimibe inhibits the intestinal absorption of cholesterol by binding Niemann-Pick C1 like-1 ( 33 ). In addition, because Niemann-Pick C1 like-1 is expressed in hepatocytes and biliary epithelial cells as well as in enterocytes ( 34 ), ezetimibe may interrupt the hepatic recycling of cholesterol secreted into bile and taken up by biliary duct epithelium.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Ioannou

Rooyen

Savard

et al. 2015

Journal of Lipid Research

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Nonalcoholic fatty liver disease (NAFLD) is characterized by increased lipid deposition within hepatocytes attributable to metabolic causes in the absence of viral hepatitis or liver disorders caused by excessive alcohol or toxic drug consumption or other liver disorders. In the majority of patients, NAFLD manifests histologically as "simple steatosis" defi ned as hepatic steatosis without substantial infl ammation or fi brosis. Simple steatosis carries a very low risk of progression to cirrhosis and liver dysfunction ( 1 ). However, 10-30% of patients with NAFLD have or develop nonalcoholic steatohepatitis (NASH), characterized by hepatic lobular infl ammation and fi brosis in addition to steatosis. Progression to cirrhosis occurs in a proportion of patients ( 1, 2 ). The factor(s) responsible for the development of progressive NASH, as opposed to simple steatosis, remain unclear. A prominent concept that has been invoked to explain the development of NASH is that of lipotoxicity. Hepatic lipotoxicity implies that exposure to, or accumulation of, certain lipid species within hepatic cells may directly cause cellular toxicity or act in a proinfl ammatory or profi brotic manner. According to the hypothesis of hepatic lipotoxicity, NASH develops when the liver is exposed to lipotoxic lipid species, whereas simple steatosis develops in response to over-nutrition when the liver is not signifi cantly exposed to lipotoxic lipid species. It is generally accepted that triglycerides, which constitute the majority of hepatic lipids in NASH and simple steatosis, are a "safe" storage lipid with little or no lipotoxic potential. Relatively small quantities of other lipotoxic lipid species may exert a disproportionate impact in the development of NASH.Lipidomic analyses of human livers with NAFLD reported that levels of free (unesterifi ed) cholesterol (FC) were increased in NASH but not in simple steatosis, whereas levels of Abstract Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic

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“…These studies were extended to include binding to mouse, hamster, rabbit, and canine NPC1L1, which correlated to the in vivo activity of ezetimibe 20) . Binding studies with multiple species NPC1L1 orthologs also demonstrated that the binding affinity for the glucuronide metabolite was 2-10 fold higher than ezetimibe.…”

Section: Discovery Of the Molecular Target Of Zetiamentioning

confidence: 99%

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Davis¹,

Veltri²

2007

J Atheroscler Thromb

143

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Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals. . Zetia was identified through the characterization of the active biliary metabolites of its predecessor, SCH 48461, and extensive structure-activity relationship information obtained from a seven day cholesterol-fed hamster model 2) . Ezetimibe dose-dependently inhibited diet-induced hypercholesterolemia in hamsters with an ED50 of 0.04 mg/kg. In an acute model of intestinal absorption using radiolabeled cholesterol in rats, ezetimibe inhibited the appearance of radiolabeled cholesterol in plasma with an ED50 of 0.0015 mg/kg ninety minutes after dosing, indicating that the onset of activity was rapid 3) . Ezetimibe has proven to be most potent pre-clinically in cholesterol-fed rhesus monkeys with an ED50 0.0005 mg/kg/day. A single dose of the ezetimibe analog, SCH 48461, administered to cynomolgus monkeys fed a single cholesterol-containing meal caused a significant reduction of cholesterol in chylomicrons and chylomicron remnants during the postprandial phase without affecting triglyceride content 4) . Ezetimibe selectively inhibits the transport of cholesterol across the intestinal wall. Ezetimibe does not affect intestinal cholesteryl ester hydrolysis and the absorption of fatty acids thus generated. The free cholesterol from this hydrolysis, however, was not absorbed J Atheroscler

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In Vivo Responsiveness to Ezetimibe Correlates with Niemann-Pick C1 Like-1 (NPC1L1) Binding Affinity: Comparison of Multiple Species NPC1L1 Orthologs

Cited by 59 publications

References 36 publications

Ezetimibe interferes with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum in CaCo-2 cells

Ezetimibe interferes with cholesterol trafficking from the plasma membrane to the endoplasmic reticulum in CaCo-2 cells

Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

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