Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacyl...Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacylglycerols tributyrin(Tb)and tripropionin(Tp)are odorless and can be directly used as healthy supplements.In view that no study has investigated the relative biological potency of Tb and Tp,the present study was designed to compare the effects of Tp and Tb on plasma cholesterol and gut microbiota using hypercholesterolemic hamsters as a model.Male golden hamsters were randomly allocated to 6 groups fed one of the following 6 diets,namely,low-cholesterol diet(LCD),high-cholesterol diet(HCD),HCD+0.5%Tp(LTp),HCD+1%Tp(HTp),HCD+0.5%Tb(LTb),and HCD+1%Tb(HTb).Results showed that Tb administration at 1%could significantly reduce plasma total cholesterol(TC),non-high-density lipoprotein cholesterol(non-HDLC),and the ratio of non-HDLC to HDLC,whereas Tp supplementation had no effect.Mechanistically,Tb but not Tp could decrease plasma cholesterol by increasing the excretion of fecal bile acids via upregulating gene expression of cholesterol 7α-hydroxylase(CYP7A1)and liver X receptor alpha(LXRα).In addition,Tb supplementation at 1%could increase the gut microbiota diversity,reduce the ratio of Firmicutes/Bacteroidetes and favorably increase the abundance of beneficial microbial genera Bifidobacterium.In conclusion,dietary Tb supplementation was more effective than Tp in mitigating hypercholesterolemia by increasing the excretion of fecal bile acids and favorably modulating gut microbiota.展开更多
Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol ...Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.展开更多
Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the ...Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the aqueous extract of I.batatas leaves in a rat model of diet-induced hypercholesterolemia.Methods:Hypercholesterolemia was induced in male Wistar rats by exclusive feeding with a cholesterolenriched(1%)standard diet for four weeks.Then,rats were treated once daily(per os)with I.batatas extract at doses of 400,500 and 600 mg/kg or with atorvastatin(2 mg/kg),for four weeks.Following treatment,animals were observed for another four weeks and then sacrificed.Aortas were excised and processed for histopathological studies,and blood glucose level and lipid profile were measured.Results:Hypercholesterolemic animals experienced a 21.5%faster increase in body weight,significant increases in blood glucose and blood lipids(148.94%triglycerides,196.97%high-density lipoprotein cholesterol,773.04%low-density lipoprotein cholesterol,148.93%very low-density lipoprotein cholesterol and 210.42%total cholesterol),and increases in aorta thickness and atherosclerotic plaque sizes compared to rats fed standard diet.Treatment of hypercholesterolemic rats with the extract mitigated these alterations and restored blood glucose and blood lipid levels to normocholesterolemic values.Conclusion:Our findings suggest that I.batatas leaves have hypolipidemic and anti-atherosclerogenic properties and justify their use in traditional medicine.展开更多
Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primar...Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.展开更多
Surgical intervention is currently the primary treatment for hepatolithiasis;how-ever,some patients still experience residual stones and high recurrence rates after surgery.Cholesterol metabolism seems to play an impo...Surgical intervention is currently the primary treatment for hepatolithiasis;how-ever,some patients still experience residual stones and high recurrence rates after surgery.Cholesterol metabolism seems to play an important role in hepatoli-thiasis pathogenesis.A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis.Therefore,regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery.Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepato-lithiasis.This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis,as well as food intake and targeted therapeutic drugs.展开更多
Unlike most plants, members of the genus Solanum produce cholesterol and use this as a precursor for steroidal glycoalkaloids. The production of the compounds begins as a branch from brassinosteroid biosynthesis, whic...Unlike most plants, members of the genus Solanum produce cholesterol and use this as a precursor for steroidal glycoalkaloids. The production of the compounds begins as a branch from brassinosteroid biosynthesis, which produces cholesterol that is further modified to produce steroidal glycoalkaloids. During the cholesterol biosynthesis pathway, genetic engineering could alter the formation of cholesterol from provitamin D3(7-dehydrocholesterol) and produce vitamin D3. Cholesterol is a precursor for many steroidal glycoalkaloids, including a-tomatine and esculeoside A. Alpha-tomatine is consumed by mammals and it can reduce cholesterol content and improve LDL:HDL ratio. When there is a high a-tomatine content, the fruit will have a bitter flavor, which together with other steroidal glycoalkaloids serving as protective and defensive compounds for tomato against insect, fungal, and bacterial pests. These compounds also affect the rhizosphere bacteria by recruiting beneficial bacteria. One of the steroidal glycoalkaloids, esculeoside A increases while fruit ripening. This review focuses on recent studies that uncovered key reactions of the production of cholesterol and steroidal glycoalkaloids in tomato connecting to human health, fruit flavor, and plant defense and the potential application for tomato crop improvement.展开更多
Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross t...Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain barrier.The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.Methods The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron microscopy.Results High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and striatum.Electron microscopy revealed that the enzyme was localized in the axon terminals.One the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and brainstem.Conclusion The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.展开更多
Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to...Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.展开更多
Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dieta...Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.展开更多
BACKGROUND Esophageal cancer(EC)is one of the most common malignancies worldwide,and lymph node(LN)metastasis remains one of the leading causes of EC recurrence.Metabolic disorders critically affect cancer progression...BACKGROUND Esophageal cancer(EC)is one of the most common malignancies worldwide,and lymph node(LN)metastasis remains one of the leading causes of EC recurrence.Metabolic disorders critically affect cancer progression,and lipid levels are closely associated with the occurrence of EC and several other tumor types.This study analyzed pretreatment lipid levels to determine their association with LN metastasis.AIM To dissect the possible mechanisms underlying LN metastasis and clarify the prognostic role of lipid profiles in EC.METHODS Serum lipid levels and clinicopathological information were retrospectively collected from 294 patients,and risk factors for LN metastasis were confirmed using a logistic regression model.Latent factors were explored using information from publicly accessible databases and immunofluorescence and immunohistochemical staining techniques.RESULTS High serum levels of low-density lipoprotein(LDL)cholesterol promote LN metastasis in EC,while high-density lipoprotein cholesterol has the opposite role.Information of a public database revealed that LDL receptors LRP5 and LRP6 are highly expressed in ECs,and LRP6 overexpression positively correlated with the infiltration of B lymphocytes and a poor prognosis.Immunofluorescence and immunohistochemical staining revealed that the expression of LRP6 and infiltrated B lymphocytes in patients with≥1 regional LN metastasis,containing N1-3(N+group)were significantly higher than those in the N0 group.LRP6 was also highly expressed in the B lymphocytes of the N+group.There was no difference in CXCL13 expression between the N+and N0 groups.However,CXCR5 expression was significantly higher in the N0 group than in the N+group.CONCLUSION High serum LDL levels can promote LN metastasis in EC,and the mechanisms may be related to LRP6 expression and the infiltration of B lymphocytes.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
Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improv...Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.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
Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by...Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.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
Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease. With respect to cardiovascular disease, biliary cholesterol...Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease. With respect to cardiovascular disease, biliary cholesterol secretion is regarded as the f inal step for the elimination of cholesterol originating from cholesterol-laden macrophage foam cells in the vessel wall in a pathway named reverse cholesterol transport. On the other hand, cholesterol hypersecretion into the bile is considered the main pathophysiological determinant of cholesterol gallstone formation. This review summarizes current knowledge on the origins of cholesterol secreted into the bile as well as the relevant processes and transporters involved. Next to the established ATP-binding cassette (ABC) transporters mediating the biliary secretion of bile acids (ABCB11), phospholipids (ABCB4) and cholesterol (ABCG5/G8), special attention is given to emerging proteins that modulate or mediate biliary cholesterol secretion. In this regard, the potential impact of the phosphatidylserine flippase ATPase class Ⅰ type 8B member 1, the Niemann Pick C1-like protein 1 that mediatescholesterol absorption and the high density lipoprotein cholesterol uptake receptor, scavenger receptor class B type Ⅰ, is discussed.展开更多
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop...Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TRβ1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TRβ1-modulating thyromimetics on RCT in various animal models and in humans.展开更多
Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-ric...Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumu- lation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocho-lesterolemic strategies will also be introduced.展开更多
基金supported by Hong Kong Research Grants Council General Research Fund(14104923).
文摘Propionate and butyrate are proven capable of decreasing plasma cholesterol.However,their undesired odor and unpleasant smell limit their direct application as a dietary supplement.In contrast,their respective triacylglycerols tributyrin(Tb)and tripropionin(Tp)are odorless and can be directly used as healthy supplements.In view that no study has investigated the relative biological potency of Tb and Tp,the present study was designed to compare the effects of Tp and Tb on plasma cholesterol and gut microbiota using hypercholesterolemic hamsters as a model.Male golden hamsters were randomly allocated to 6 groups fed one of the following 6 diets,namely,low-cholesterol diet(LCD),high-cholesterol diet(HCD),HCD+0.5%Tp(LTp),HCD+1%Tp(HTp),HCD+0.5%Tb(LTb),and HCD+1%Tb(HTb).Results showed that Tb administration at 1%could significantly reduce plasma total cholesterol(TC),non-high-density lipoprotein cholesterol(non-HDLC),and the ratio of non-HDLC to HDLC,whereas Tp supplementation had no effect.Mechanistically,Tb but not Tp could decrease plasma cholesterol by increasing the excretion of fecal bile acids via upregulating gene expression of cholesterol 7α-hydroxylase(CYP7A1)and liver X receptor alpha(LXRα).In addition,Tb supplementation at 1%could increase the gut microbiota diversity,reduce the ratio of Firmicutes/Bacteroidetes and favorably increase the abundance of beneficial microbial genera Bifidobacterium.In conclusion,dietary Tb supplementation was more effective than Tp in mitigating hypercholesterolemia by increasing the excretion of fecal bile acids and favorably modulating gut microbiota.
基金supported by the National Natural Science Foundation of China,No.82072110Suzhou Municipal Science and Technology Bureau,No.SKJY2021046+1 种基金Shanghai Key Lab of Forensic Medicine&Key Lab of Forensic Science,Ministry of Justice,China(Academy of Forensic Science),No.KF202201a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(all to TW).
文摘Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.
基金partly funded by the Faculty of Science,University of Ngaoundere。
文摘Objective:Ipomoea batatas(L.)Lam.is a food plant used in African traditional medicine to treat cardiovascular diseases and related conditions.We assessed the hypolipidemic and anti-atherosclerogenic properties of the aqueous extract of I.batatas leaves in a rat model of diet-induced hypercholesterolemia.Methods:Hypercholesterolemia was induced in male Wistar rats by exclusive feeding with a cholesterolenriched(1%)standard diet for four weeks.Then,rats were treated once daily(per os)with I.batatas extract at doses of 400,500 and 600 mg/kg or with atorvastatin(2 mg/kg),for four weeks.Following treatment,animals were observed for another four weeks and then sacrificed.Aortas were excised and processed for histopathological studies,and blood glucose level and lipid profile were measured.Results:Hypercholesterolemic animals experienced a 21.5%faster increase in body weight,significant increases in blood glucose and blood lipids(148.94%triglycerides,196.97%high-density lipoprotein cholesterol,773.04%low-density lipoprotein cholesterol,148.93%very low-density lipoprotein cholesterol and 210.42%total cholesterol),and increases in aorta thickness and atherosclerotic plaque sizes compared to rats fed standard diet.Treatment of hypercholesterolemic rats with the extract mitigated these alterations and restored blood glucose and blood lipid levels to normocholesterolemic values.Conclusion:Our findings suggest that I.batatas leaves have hypolipidemic and anti-atherosclerogenic properties and justify their use in traditional medicine.
基金financially supported by the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)China Postdoctoral Science Foundation,No.2022M711733(to ZZ)+2 种基金the National Natural Science Foundation of China,No.82160920(to ZZ)Hebei Postdoctoral Scientific Research Project,No.B2022003040(to ZZ)Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine(to WP)。
文摘Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
基金Supported by Hebei Natural Science Foundation,No.H2022206539Hebei Provincial Government Funded Clinical Talents Training Project,No.ZF2023143.
文摘Surgical intervention is currently the primary treatment for hepatolithiasis;how-ever,some patients still experience residual stones and high recurrence rates after surgery.Cholesterol metabolism seems to play an important role in hepatoli-thiasis pathogenesis.A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis.Therefore,regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery.Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepato-lithiasis.This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis,as well as food intake and targeted therapeutic drugs.
文摘Unlike most plants, members of the genus Solanum produce cholesterol and use this as a precursor for steroidal glycoalkaloids. The production of the compounds begins as a branch from brassinosteroid biosynthesis, which produces cholesterol that is further modified to produce steroidal glycoalkaloids. During the cholesterol biosynthesis pathway, genetic engineering could alter the formation of cholesterol from provitamin D3(7-dehydrocholesterol) and produce vitamin D3. Cholesterol is a precursor for many steroidal glycoalkaloids, including a-tomatine and esculeoside A. Alpha-tomatine is consumed by mammals and it can reduce cholesterol content and improve LDL:HDL ratio. When there is a high a-tomatine content, the fruit will have a bitter flavor, which together with other steroidal glycoalkaloids serving as protective and defensive compounds for tomato against insect, fungal, and bacterial pests. These compounds also affect the rhizosphere bacteria by recruiting beneficial bacteria. One of the steroidal glycoalkaloids, esculeoside A increases while fruit ripening. This review focuses on recent studies that uncovered key reactions of the production of cholesterol and steroidal glycoalkaloids in tomato connecting to human health, fruit flavor, and plant defense and the potential application for tomato crop improvement.
基金supported by the National Natural Science Foundation of China(No.30901940)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Education Ministry of China
文摘Objective Cholesterol 24-hydroxylase catalyzes the conversion of cholesterol to 24-hydroxycholesterol,which is a major pathway for cholesterol elimination from the brain,since 24-hydroxycholesterol can readily cross the blood brain barrier.The present study aimed to elucidate the distribution of cholesterol 24-hydroxylase in the monkey brain.Methods The distribution of cholesterol 24-hydroxylase in the monkey brain was examined using Western blot and immunohistochemistry methods,and was observed under light microscopy and electron microscopy.Results High levels of cholesterol 24-hydroxylase were observed in projection neurons and neuropil in structures derived from telencephalon,including the cerebral neocortex,hippocampus,amygdala,nucleus basalis of Meynert,and striatum.Electron microscopy revealed that the enzyme was localized in the axon terminals.One the other hand,cholesterol 24-hydroxylase was expressed at a lower level in the thalamus,globus pallidus and brainstem.Conclusion The high level of cholesterol 24-hydroxylase in the telencephalon possibly reflects a high rate of cholesterol turnover in this part of brain.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
基金National Key Research and Development Program of China(Grant No.2022YFC3501700)the Beijing Municipal Natural Science Foundation(Grant No.7144219).
文摘Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.
基金supported by Hong Kong Research Grants Council General Research Fund(CUHK 14102321,14103722 and 14104923)。
文摘Oxidized cholesterol(OXC)is a harmful dietary substance.Although the consumption of OXC has been associated with colonic inflammation,related underlying mechanisms are still limited.We evaluated the influence of dietary OXC on gut health and ecology by applying the murine model.Results showed that the thickness of the mucus layer was significantly reduced in healthy mice treated with OXC.Short-term intake of OXC did not influence the expression of pro-inflammatory factors in healthy mice but it induced the decrease of Muc2 expression in the proximal colon,accompanied by an increase in the abundance of 2 mucusdegrading bacteria,namely Akkermansia muciniphila and Bacteroides acidifaciens.Consistently,oral exposure of OXC promoted mucus barrier erosion in dextran sulfate sodium(DSS)-induced colitis mice and facilitated bacteria infiltration in the colon.The adverse effect of OXC on mucus layer disappeared in antibiotics-treated healthy mice,suggesting that the damaging effect of OXC on the gut mucus layer was not direct and instead was mediated by causing microbiota dysbiosis.Finally,the impact of OXC on the mucus layer and colitis was partly alleviated by green tea catechins.These studies demonstrated that the OXC-induced mucus barrier damage was mainly induced by the dysregulation of gut microbiota at least in this mouse model.
文摘BACKGROUND Esophageal cancer(EC)is one of the most common malignancies worldwide,and lymph node(LN)metastasis remains one of the leading causes of EC recurrence.Metabolic disorders critically affect cancer progression,and lipid levels are closely associated with the occurrence of EC and several other tumor types.This study analyzed pretreatment lipid levels to determine their association with LN metastasis.AIM To dissect the possible mechanisms underlying LN metastasis and clarify the prognostic role of lipid profiles in EC.METHODS Serum lipid levels and clinicopathological information were retrospectively collected from 294 patients,and risk factors for LN metastasis were confirmed using a logistic regression model.Latent factors were explored using information from publicly accessible databases and immunofluorescence and immunohistochemical staining techniques.RESULTS High serum levels of low-density lipoprotein(LDL)cholesterol promote LN metastasis in EC,while high-density lipoprotein cholesterol has the opposite role.Information of a public database revealed that LDL receptors LRP5 and LRP6 are highly expressed in ECs,and LRP6 overexpression positively correlated with the infiltration of B lymphocytes and a poor prognosis.Immunofluorescence and immunohistochemical staining revealed that the expression of LRP6 and infiltrated B lymphocytes in patients with≥1 regional LN metastasis,containing N1-3(N+group)were significantly higher than those in the N0 group.LRP6 was also highly expressed in the B lymphocytes of the N+group.There was no difference in CXCL13 expression between the N+and N0 groups.However,CXCR5 expression was significantly higher in the N0 group than in the N+group.CONCLUSION High serum LDL levels can promote LN metastasis in EC,and the mechanisms may be related to LRP6 expression and the infiltration of B lymphocytes.
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.
基金supported by the National Natural Science Foundation of China funded project(32172627)Chongqing Modern Tea Technology System for Efficient Agriculture in Mountainous Areas 2022[8]the Germplasm Creation Research Program of Southwest University。
文摘Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.
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.
基金supported by the National Natural Science Foundation of ChinaNo.81971826 (to AG)+5 种基金the China Postdoctoral Science FoundationNo.2020M681 689 (to YH)the Scientific Research Project of The Health Commission of Jiangsu ProvinceNo.ZDB2020003 (to AG)the Basic Scientific Research Projects of NantongNo.JC2020041 (to YH)
文摘Astrocytes are important cellular centers of cholesterol synthesis and metabolism that help maintain normal physiological function at the organism level.Spinal cord injury results in aberrant cholesterol metabolism by astrocytes and excessive production of oxysterols,which have profound effects on neuropathology.25-Hydroxycholesterol(25-HC),the main product of the membrane-associated enzyme cholesterol-25-hydroxylase(CH25H),plays important roles in mediating neuroinflammation.However,whether the abnormal astrocyte cholesterol metabolism induced by spinal cord injury contributes to the production of 25-HC,as well as the resulting pathological effects,remain unclear.In the present study,spinal cord injury-induced activation of thrombin was found to increase astrocyte CH25H expression.A protease-activated receptor 1 inhibitor was able to attenuate this effect in vitro and in vivo.In cultured primary astrocytes,thrombin interacted with protease-activated receptor 1,mainly through activation of the mitogen-activated protein kinase/nuclear factor-kappa B signaling pathway.Conditioned culture medium from astrocytes in which ch25h expression had been knocked down by siRNA reduced macrophage migration.Finally,injection of the protease activated receptor 1 inhibitor SCH79797 into rat neural sheaths following spinal cord injury reduced migration of microglia/macrophages to the injured site and largely restored motor function.Our results demonstrate a novel regulatory mechanism for thrombin-regulated cholesterol metabolism in astrocytes that could be used to develop anti-inflammatory drugs to treat patients with spinal cord injury.
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.
基金Supported by A grant from the Netherlands Organization for Scientif ic Research (NWO, VIDI Grant 917-56-358)
文摘Biliary cholesterol secretion is a process important for 2 major disease complexes, atherosclerotic cardiovascular disease and cholesterol gallstone disease. With respect to cardiovascular disease, biliary cholesterol secretion is regarded as the f inal step for the elimination of cholesterol originating from cholesterol-laden macrophage foam cells in the vessel wall in a pathway named reverse cholesterol transport. On the other hand, cholesterol hypersecretion into the bile is considered the main pathophysiological determinant of cholesterol gallstone formation. This review summarizes current knowledge on the origins of cholesterol secreted into the bile as well as the relevant processes and transporters involved. Next to the established ATP-binding cassette (ABC) transporters mediating the biliary secretion of bile acids (ABCB11), phospholipids (ABCB4) and cholesterol (ABCG5/G8), special attention is given to emerging proteins that modulate or mediate biliary cholesterol secretion. In this regard, the potential impact of the phosphatidylserine flippase ATPase class Ⅰ type 8B member 1, the Niemann Pick C1-like protein 1 that mediatescholesterol absorption and the high density lipoprotein cholesterol uptake receptor, scavenger receptor class B type Ⅰ, is discussed.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
基金Supported by Research Award from KaroBio AB, Sweden (to Parini P)
文摘Reverse cholesterol transport (RCT) is a complex process which transfers cholesterol from peripheral cells to the liver for subsequent elimination from the body via feces. Thyroid hormones (THs) affect growth, develop- ment, and metabolism in almost all tissues. THs exert their actions by binding to thyroid hormone receptors (TRs). There are two major subtypes of TRs, TRα and TRβ, and several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). Activation of TRα1 affects heart rate, whereas activation of TRβ1 has positive effects on lipid and lipoprotein metabolism. Consequently, particular interest has been focused on the development of thyromimetic compounds targeting TRβ1, not only because of their ability to lower plasma cholesterol but also due their ability to stimulate RCT, at least in pre-clinical models. In this review we focus on THs, TRs, and on the effects of TRβ1-modulating thyromimetics on RCT in various animal models and in humans.
文摘Cholesterol plays several structural and metabolic roles that are vital for human biology. It spreads along the entire plasma membrane of the cell, modulating fluidity and concentrating in specialized sphingolipid-rich domains called rafts and caveolae. Cholesterol is also a substrate for steroid hormones. However, too much cholesterol can lead to pathological pictures such as atherosclerosis, which is a consequence of the accumu- lation of cholesterol into the cells of the artery wall. The liver is considered to be the metabolic power station of mammalians, where cholesterol homeostasis relies on an intricate network of cellular processes whose deregulations can lead to several life-threatening pathologies, such as familial and age-related hypercholesterolemia. Cholesterol homeostasis maintenance is carried out by: biosynthesis, via 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity; uptake, through low density lipoprotein receptors (LDLr); lipoprotein release in the blood; storage by esterification; and degradation and conversion into bile acids. Both HMGR and LDLr are transcribed as a function of cellular sterol amount by a family of transcription factors called sterol regulatory element binding proteins that are responsible for the maintenance of cholesterol homeostasis through an intricate mechanism of regulation. Cholesterol obtained by hepatic de novo synthesis can be esterified and incorporated into apolipoprotein B-100-containing very low density lipoproteins, which are then secreted into the bloodstream for transport to peripheral tissues. Moreover, dietary cholesterol is transferred from the intestine to the liver by high density lipoproteins (HDLs); all HDL particles are internalized in the liver, interacting with the hepatic scavenger receptor (SR-B1). Here we provide an updated overview of liver cholesterol metabolism regulation and deregulation and the causes of cholesterol metabolism-related diseases. Moreover, current pharmacological treatment and novel hypocho-lesterolemic strategies will also be introduced.
