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
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
Objective To investigate the role and mechanism of baicalin in regulating the NOD-like receptor 3(NLRP3)/cysteinyl aspartate specific proteinase 1 (caspase-1)/gasdermin D (GSDMD) pathway to mediate cholesterol efflux ...Objective To investigate the role and mechanism of baicalin in regulating the NOD-like receptor 3(NLRP3)/cysteinyl aspartate specific proteinase 1 (caspase-1)/gasdermin D (GSDMD) pathway to mediate cholesterol efflux to improve atherosclerosis (AS).展开更多
Excess cholesterol in macrophages is progressively converted into cholesterol crystals(CCs),promoting the transformation of macrophages into foam cells,a key process that drives the development of atherosclerosis(AS)....Excess cholesterol in macrophages is progressively converted into cholesterol crystals(CCs),promoting the transformation of macrophages into foam cells,a key process that drives the development of atherosclerosis(AS).β-cyclodextrin(β-CD)is a potent solubilizer of CCs and has been shown that could promote the efflux of CCs from foam cells.However,β-CD randomized extracts cholesterol in vivo,which reduces the therapeutic effect for AS plaque lesion and biosafety.Here,we constructed phosphatidylserine-targeting peptide(PS peptide)modified polyethylene glycol(PEG)-CD and ferrocene-modified phenylboronic acid(Fc-PBA)as a reactive oxygen species(ROS)-responsive switch(“OFF-ON”).Under physiological condition,Fc of Fc-PBA effectively closes the cavity ofβ-CD and loads resveratrol(RVT)via borate bonds(RVT NPs).The PS peptide on the surface of nanoparticles was conjugated with the phosphatidylserine on the inner leaflet of macrophage membrane(MM)to harvest the right-side-out biomimetic membrane camouflaged nanoparticles(MM@RVT NPs),which could enhance the delivery to the inflammatory sites of AS plaques.When MM@RVT NPs arrived the plaque,the breakdown of MM@RVT NPs resulting from the oxidation of Fc-PBA,restored theβ-CD lumen to dissolve CCs into free cholesterol and enhanced its efflux.Moreover,RVT was timely released to further enhance the expression of receptors associated with mediating cholesterol efflux.Besides,RVT also reduced the oxidative stress,and promoted the phenotypic conversion of macrophages from M1 to M2 type for alleviating inflammation in AS lesions.Therefore,MM@RVT NPs could be an intelligent nanoplatform for promoting the efficient AS management.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
Tangier disease is caused by mutations in ATP binding cassette transporter A1( ABCA1). ABCA1 interacts with lipid-free apolip oproteins, promoting phospholipid and cholesterol efflux from cells and giving r ise to HDL...Tangier disease is caused by mutations in ATP binding cassette transporter A1( ABCA1). ABCA1 interacts with lipid-free apolip oproteins, promoting phospholipid and cholesterol efflux from cells and giving r ise to HDL particles. ABCA1 may act as a phospholipid translocase facilitating p hospholipid binding to apoA-I. ABCA1 gene expression is upregulated in cholester ol-loaded cells as a result of activation of LXR/RXR-mediated gene transcription . LXR and RXR coordinately induce a battery of genes mediating cellular choleste rol efflux, centripetal cholesterol transport, and cholesterol excretion in bile . Small-molecule activators of LXR/RXR or other stimulators of macrophage or int estinal cholesterol efflux hold great promise as future treatments for atheroscl erosis.展开更多
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.
文摘Objective To investigate the role and mechanism of baicalin in regulating the NOD-like receptor 3(NLRP3)/cysteinyl aspartate specific proteinase 1 (caspase-1)/gasdermin D (GSDMD) pathway to mediate cholesterol efflux to improve atherosclerosis (AS).
基金supported by grants from the Fundamental Research Funds for the National Key R&D Project(No.2022YFF0710700)the National Natural Science Foundation of China(Nos.31971301,52303146,and 32171324)+5 种基金Natural Science Foundation of Chongqing(No.cstc2021jcyj-cxttX0002)Chongqing medical scientific research project(Joint project of Chongqing Health Commission and Science and Technology Bureau)(No.2024ZDXM006)Fundamental Research Funds for Central Universities(No.2024CDJXY017)JinFeng Laboratory of Chongqing(No.JFLKYXM202303AZ-204)Science and Techology Research Program of Chongqing Municipal Education Commission(No.KJQN202300114)National Defense Foundation Strengthening Program(No.2022-JCJQ-ZD-224-12).In addition,we would like to thank Mr.Zhang Bin at Analytical and Testing Center of Chongqing University for their assistance with TEM.
文摘Excess cholesterol in macrophages is progressively converted into cholesterol crystals(CCs),promoting the transformation of macrophages into foam cells,a key process that drives the development of atherosclerosis(AS).β-cyclodextrin(β-CD)is a potent solubilizer of CCs and has been shown that could promote the efflux of CCs from foam cells.However,β-CD randomized extracts cholesterol in vivo,which reduces the therapeutic effect for AS plaque lesion and biosafety.Here,we constructed phosphatidylserine-targeting peptide(PS peptide)modified polyethylene glycol(PEG)-CD and ferrocene-modified phenylboronic acid(Fc-PBA)as a reactive oxygen species(ROS)-responsive switch(“OFF-ON”).Under physiological condition,Fc of Fc-PBA effectively closes the cavity ofβ-CD and loads resveratrol(RVT)via borate bonds(RVT NPs).The PS peptide on the surface of nanoparticles was conjugated with the phosphatidylserine on the inner leaflet of macrophage membrane(MM)to harvest the right-side-out biomimetic membrane camouflaged nanoparticles(MM@RVT NPs),which could enhance the delivery to the inflammatory sites of AS plaques.When MM@RVT NPs arrived the plaque,the breakdown of MM@RVT NPs resulting from the oxidation of Fc-PBA,restored theβ-CD lumen to dissolve CCs into free cholesterol and enhanced its efflux.Moreover,RVT was timely released to further enhance the expression of receptors associated with mediating cholesterol efflux.Besides,RVT also reduced the oxidative stress,and promoted the phenotypic conversion of macrophages from M1 to M2 type for alleviating inflammation in AS lesions.Therefore,MM@RVT NPs could be an intelligent nanoplatform for promoting the efficient AS management.
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Tangier disease is caused by mutations in ATP binding cassette transporter A1( ABCA1). ABCA1 interacts with lipid-free apolip oproteins, promoting phospholipid and cholesterol efflux from cells and giving r ise to HDL particles. ABCA1 may act as a phospholipid translocase facilitating p hospholipid binding to apoA-I. ABCA1 gene expression is upregulated in cholester ol-loaded cells as a result of activation of LXR/RXR-mediated gene transcription . LXR and RXR coordinately induce a battery of genes mediating cellular choleste rol efflux, centripetal cholesterol transport, and cholesterol excretion in bile . Small-molecule activators of LXR/RXR or other stimulators of macrophage or int estinal cholesterol efflux hold great promise as future treatments for atheroscl erosis.
