7-Ketophytosterols are the major oxidation products of phytosterols in foods, which have been associated with atherosclerosis. However, their absorption mechanism remains unclear. The aim of our work was to investigat...7-Ketophytosterols are the major oxidation products of phytosterols in foods, which have been associated with atherosclerosis. However, their absorption mechanism remains unclear. The aim of our work was to investigate the absorption mechanism of 7-ketophytosterols and their effects on the cholesterol transport using Caco-2 cell model. The absorption percentage of 7-ketositosterol and 7-ketocampesterol was 1.16%-1.68% and 1.18%-2.23% respectively in the Caco-2 model, which is higher than that of their parent phytosterols, but lower than cholesterol-d7. The apparent permeability of 7-ketositosterol and 7-ketocampesterol at 30 μmol/L in the basolateral(BL)-to-apical(AP)direction were 0.42-and 0.55-fold of that in the AP-to-BL direction, indicating an active intake in the permeation mechanism of 7-ketophytosterols. Ezetimibe could significantly inhibit the transport of 7-ketophytosterols(P < 0.05), which means that their transport depends on niemann-pick c1-like 1(NPC1L1)protein. The transport of cholesterol-d7 was significantly inhibited by 7-ketophytosterols(P < 0.05). Taken together, this study deepened our understanding of the absorption mechanism of common food-born 7-ketophytosterols and provides useful information on the inhibition of 7-ketophytosterols absorption.展开更多
The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remn...The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.展开更多
A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,...A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,a new series of analogs was designed and synthesized.展开更多
Background Coronary heart disease （CHD） risk increases with age; yet lipid-lowering therapies are significantly under-utilized in patients 〉 65 years. The objective was to evaluate the safety and efficacy of lipid-...Background Coronary heart disease （CHD） risk increases with age; yet lipid-lowering therapies are significantly under-utilized in patients 〉 65 years. The objective was to evaluate the safety and efficacy of lipid-lowering therapies in older patients treated with atorvastatin 10 nag ＋ ezetimibe 10 mg （EZ/Atorva） vs. increasing the atorvastatin dose to 40 mg, Methods Patients 〉 65 years with atherosclerotic vascular disease （LDL-C ≥1.81 mmol/L） or at high risk for coronary heart disease （LDL-C 〉 2.59 mmol/L） were randomized to EZ/Atorva for 12 wk vs. uptitration to atorvastatin 20 nag for 6 wk followed by atorvastatin 40 nag for 6 wk. The percent change in LDL-C and other lipid parameters and percent patients achieving prespecified LDL-C levels were assessed after 12 wk. Results EZ/Atorva produced greater reductions in most lipid parameters vs. uptitration of atorvastatin in patients 〉 75 years （n = 228）, generally consistent with patients 65-74 years （n = 812）. More patients achieved LDL-C targets with combination therapy vs. monotherapy in both age groups at 6 wk and in patients 〉 75 years at 12 wk. At 12 wk, more patients 〉 75 years achieved LDL-C targets with monotherapy vs. combination therapy. EZ/Atorva produced more favorable improvements in most lipids vs. doubling or quadrupling the atorvastatin dose in patients 〉 75 years, generally consistent with the findings in patients 65-74 years. Conclusions Our results extended previous findings demonstrating that ezetimibe added to a statin provided a generally well-tolerated therapeutic option for improving the lipid profile in patients 65 to 74 years and 〉 75 years of age.展开更多
More than twenty years ago,knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholestero...More than twenty years ago,knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholesterol absorption inhibitor to date–ezetimibe.Since then,ezetimibe has become a well-recognized player in lipid-lowering therapy.Recent findings of IMPROVE-IT and EWTOPIA 75 imply that elderly patients over the age of 75 years in particular benefit from ezetimibe.This review summarizes the evidence,discusses the possible underlying pathophysiological mechanisms and calls for a change in future dyslipidemia guidelines.展开更多
基金supported by the National Natural Science Foundation of China (32072179)Zhejiang Provincial Natural Science Foundation of China (LD21C200001)。
文摘7-Ketophytosterols are the major oxidation products of phytosterols in foods, which have been associated with atherosclerosis. However, their absorption mechanism remains unclear. The aim of our work was to investigate the absorption mechanism of 7-ketophytosterols and their effects on the cholesterol transport using Caco-2 cell model. The absorption percentage of 7-ketositosterol and 7-ketocampesterol was 1.16%-1.68% and 1.18%-2.23% respectively in the Caco-2 model, which is higher than that of their parent phytosterols, but lower than cholesterol-d7. The apparent permeability of 7-ketositosterol and 7-ketocampesterol at 30 μmol/L in the basolateral(BL)-to-apical(AP)direction were 0.42-and 0.55-fold of that in the AP-to-BL direction, indicating an active intake in the permeation mechanism of 7-ketophytosterols. Ezetimibe could significantly inhibit the transport of 7-ketophytosterols(P < 0.05), which means that their transport depends on niemann-pick c1-like 1(NPC1L1)protein. The transport of cholesterol-d7 was significantly inhibited by 7-ketophytosterols(P < 0.05). Taken together, this study deepened our understanding of the absorption mechanism of common food-born 7-ketophytosterols and provides useful information on the inhibition of 7-ketophytosterols absorption.
基金Supported by grant 2001B043 from the Netherlands Heart Foundation
文摘The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.
文摘A convenient method for the synthesis of ezetimibe analogs as cholesterol absorption inhibitors was described.The key step in the synthesis was the intramolecular ring formation through Mitsunobu reaction.Furthermore,a new series of analogs was designed and synthesized.
文摘Background Coronary heart disease （CHD） risk increases with age; yet lipid-lowering therapies are significantly under-utilized in patients 〉 65 years. The objective was to evaluate the safety and efficacy of lipid-lowering therapies in older patients treated with atorvastatin 10 nag ＋ ezetimibe 10 mg （EZ/Atorva） vs. increasing the atorvastatin dose to 40 mg, Methods Patients 〉 65 years with atherosclerotic vascular disease （LDL-C ≥1.81 mmol/L） or at high risk for coronary heart disease （LDL-C 〉 2.59 mmol/L） were randomized to EZ/Atorva for 12 wk vs. uptitration to atorvastatin 20 nag for 6 wk followed by atorvastatin 40 nag for 6 wk. The percent change in LDL-C and other lipid parameters and percent patients achieving prespecified LDL-C levels were assessed after 12 wk. Results EZ/Atorva produced greater reductions in most lipid parameters vs. uptitration of atorvastatin in patients 〉 75 years （n = 228）, generally consistent with patients 65-74 years （n = 812）. More patients achieved LDL-C targets with combination therapy vs. monotherapy in both age groups at 6 wk and in patients 〉 75 years at 12 wk. At 12 wk, more patients 〉 75 years achieved LDL-C targets with monotherapy vs. combination therapy. EZ/Atorva produced more favorable improvements in most lipids vs. doubling or quadrupling the atorvastatin dose in patients 〉 75 years, generally consistent with the findings in patients 65-74 years. Conclusions Our results extended previous findings demonstrating that ezetimibe added to a statin provided a generally well-tolerated therapeutic option for improving the lipid profile in patients 65 to 74 years and 〉 75 years of age.
文摘More than twenty years ago,knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholesterol absorption inhibitor to date–ezetimibe.Since then,ezetimibe has become a well-recognized player in lipid-lowering therapy.Recent findings of IMPROVE-IT and EWTOPIA 75 imply that elderly patients over the age of 75 years in particular benefit from ezetimibe.This review summarizes the evidence,discusses the possible underlying pathophysiological mechanisms and calls for a change in future dyslipidemia guidelines.
