The reverse cholesterol transport pathway (RCT) is the focus of many cholesterol-lowering therapies. By way of this pathway, excess cholesterol is collected from peripheral tissues and delivered back to the liver and ...The reverse cholesterol transport pathway (RCT) is the focus of many cholesterol-lowering therapies. By way of this pathway, excess cholesterol is collected from peripheral tissues and delivered back to the liver and gastrointestinal tract for excretion from the body. For a long time this removal via the hepatobiliary secretion was considered to be the sole route involved in the RCT. However, observations from early studies in animals and humans already pointed towards the possibility of another route. In the last few years it has become evident that a nonbiliary cholesterol secretion pathway exists in which the intestine plays a central role. This transintestinal cholesterol efflux (TICE) pathway contributes significantly to the total fecal neutral sterol excretion. Moreover, recent studies have shown that TICE is also sensitive to stimulation. As a consequence, the direct role of cholesterol secretion from blood via TICE makes the intestine a suitable and approachable target for cholesterol removal from the body and possibly reduction of atherosclerosis. In this review, the discovery and recent findings contributing to understanding the mechanism of TICE will be discussed.展开更多
The biosafety of methyl tertiary-butyl ether(MTBE),mainly used as a gasoline additive,has long been a contentious topic.In addition to its routine toxicities,MTBE has been demonstrated to disrupt glucose and lipid met...The biosafety of methyl tertiary-butyl ether(MTBE),mainly used as a gasoline additive,has long been a contentious topic.In addition to its routine toxicities,MTBE has been demonstrated to disrupt glucose and lipid metabolism and contribute to the development of type2 diabetes as well as obesity.As one of the morbidities related to dyslipidemia,atherosclerosis is worthy of being investigated under MTBE exposure.Since foam cells derived from macrophages play pivotal roles during atherosclerosis development,we studied the effects of MTBE on macrophages in vitro and assessed the effect of MTBE on atherosclerosis plaque formation with the ApoE^(-/-)mouse model in uiuo for the first time.Our results demonstrated that exposure to MTBE at environmentally relevant concentrations decreased the expression of ABCA1 and ABCG1,which are responsible for macrophage cholesterol efflux,at both mRNA and protein levels in THP-1 macrophages.Consequently,treatment with MTBE inhibited the transport of cholesterol from macrophages to High-density lipoprotein.ApoE^(-/-)mice exposed to MTBE at environmentally relevant concentrations(100,1000μg/kg)displayed significant increases in lesion area in the aorta and aortic root compared to vehicletreated ones.Further analysis indicated that MTBE exposure enhanced the macrophagespecific marker Mac-2 contents within plaques in the aortic root,implying that MTBE could promote macrophage-derived foam cell formation and thus accelerate atherosclerosis plaque formation.We for the first time demonstrated the pro-atherogenic effect of MTBE via eliciting disruption of macrophage cholesterol efflux and accelerating foam cell formation and atherosclerosis plaque development.展开更多
Reverse cholesterol transport was originally described as the high-density lipoprotein-mediated cholesterol flux from the periphery via the hepatobiliary tract to the intestinal lumen, leading to fecal excretion. Sinc...Reverse cholesterol transport was originally described as the high-density lipoprotein-mediated cholesterol flux from the periphery via the hepatobiliary tract to the intestinal lumen, leading to fecal excretion. Since the introduction of reverse cholesterol transport in the 1970s, this pathway has been intensively investigated. In this topic highlight, the classical reverse cholesterol transport concepts are discussed and the subject reverse cholesterol transport is revisited.展开更多
Cardiovascular diseases(CVDs)are the leading cause of death globally.CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease,cerebrovascular disease and rheumatic heart disease ...Cardiovascular diseases(CVDs)are the leading cause of death globally.CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease,cerebrovascular disease and rheumatic heart disease among other conditions.There are multiple independent risk factors for CVD,including hypertension,age,smoking,insulin resistance,elevated low-density lipoprotein cholesterol(LDL-C)levels,and triglyceride levels.LDL-C levels have traditionally been the target for therapies aimed at reducing CVD risk.High density lipoprotein(HDL)constitutes the only lipoprotein fraction with atheroprotective functions.Early HDL-targeted therapies have focused on increasing HDL-C levels.However,clinical trials have shown that raising HDL-C with niacin failed to achieve CVD reduction.A possible explanation for these findings is that these drugs could interfere with lipid metabolism and cause alterations in HDL structure and composition,leading to loss of functionality.As a result,targeting HDL-C levels would be insufficient to achieve CVD risk reduction,making HDL functionality a more desirable focus for HDL-directed therapies.There are several drugs which show the potential to improve HDL functionality.These drugs include molecules already approved for human use,such as statins and niacin,and particularly,compounds currently undergoing development such as apolipoprotein A-I mimetics and reconstituted HDL preparations.These therapies show promising potential to improve HDL functionality specifically.Future therapeutic strategies should incorporate HDL functionality as a main target of interest.展开更多
文摘The reverse cholesterol transport pathway (RCT) is the focus of many cholesterol-lowering therapies. By way of this pathway, excess cholesterol is collected from peripheral tissues and delivered back to the liver and gastrointestinal tract for excretion from the body. For a long time this removal via the hepatobiliary secretion was considered to be the sole route involved in the RCT. However, observations from early studies in animals and humans already pointed towards the possibility of another route. In the last few years it has become evident that a nonbiliary cholesterol secretion pathway exists in which the intestine plays a central role. This transintestinal cholesterol efflux (TICE) pathway contributes significantly to the total fecal neutral sterol excretion. Moreover, recent studies have shown that TICE is also sensitive to stimulation. As a consequence, the direct role of cholesterol secretion from blood via TICE makes the intestine a suitable and approachable target for cholesterol removal from the body and possibly reduction of atherosclerosis. In this review, the discovery and recent findings contributing to understanding the mechanism of TICE will be discussed.
基金supported by the National Key R&D Program of China(Nos.2019YFC1605800,2018YFC0406302)the National Natural Science Foundation of China(Nos.21806179,21672255)the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB14040201)。
文摘The biosafety of methyl tertiary-butyl ether(MTBE),mainly used as a gasoline additive,has long been a contentious topic.In addition to its routine toxicities,MTBE has been demonstrated to disrupt glucose and lipid metabolism and contribute to the development of type2 diabetes as well as obesity.As one of the morbidities related to dyslipidemia,atherosclerosis is worthy of being investigated under MTBE exposure.Since foam cells derived from macrophages play pivotal roles during atherosclerosis development,we studied the effects of MTBE on macrophages in vitro and assessed the effect of MTBE on atherosclerosis plaque formation with the ApoE^(-/-)mouse model in uiuo for the first time.Our results demonstrated that exposure to MTBE at environmentally relevant concentrations decreased the expression of ABCA1 and ABCG1,which are responsible for macrophage cholesterol efflux,at both mRNA and protein levels in THP-1 macrophages.Consequently,treatment with MTBE inhibited the transport of cholesterol from macrophages to High-density lipoprotein.ApoE^(-/-)mice exposed to MTBE at environmentally relevant concentrations(100,1000μg/kg)displayed significant increases in lesion area in the aorta and aortic root compared to vehicletreated ones.Further analysis indicated that MTBE exposure enhanced the macrophagespecific marker Mac-2 contents within plaques in the aortic root,implying that MTBE could promote macrophage-derived foam cell formation and thus accelerate atherosclerosis plaque formation.We for the first time demonstrated the pro-atherogenic effect of MTBE via eliciting disruption of macrophage cholesterol efflux and accelerating foam cell formation and atherosclerosis plaque development.
文摘Reverse cholesterol transport was originally described as the high-density lipoprotein-mediated cholesterol flux from the periphery via the hepatobiliary tract to the intestinal lumen, leading to fecal excretion. Since the introduction of reverse cholesterol transport in the 1970s, this pathway has been intensively investigated. In this topic highlight, the classical reverse cholesterol transport concepts are discussed and the subject reverse cholesterol transport is revisited.
文摘Cardiovascular diseases(CVDs)are the leading cause of death globally.CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease,cerebrovascular disease and rheumatic heart disease among other conditions.There are multiple independent risk factors for CVD,including hypertension,age,smoking,insulin resistance,elevated low-density lipoprotein cholesterol(LDL-C)levels,and triglyceride levels.LDL-C levels have traditionally been the target for therapies aimed at reducing CVD risk.High density lipoprotein(HDL)constitutes the only lipoprotein fraction with atheroprotective functions.Early HDL-targeted therapies have focused on increasing HDL-C levels.However,clinical trials have shown that raising HDL-C with niacin failed to achieve CVD reduction.A possible explanation for these findings is that these drugs could interfere with lipid metabolism and cause alterations in HDL structure and composition,leading to loss of functionality.As a result,targeting HDL-C levels would be insufficient to achieve CVD risk reduction,making HDL functionality a more desirable focus for HDL-directed therapies.There are several drugs which show the potential to improve HDL functionality.These drugs include molecules already approved for human use,such as statins and niacin,and particularly,compounds currently undergoing development such as apolipoprotein A-I mimetics and reconstituted HDL preparations.These therapies show promising potential to improve HDL functionality specifically.Future therapeutic strategies should incorporate HDL functionality as a main target of interest.
