The Effects of Apolipoprotein E Polymorphism on Serum Lipids, Lipoproteins and Apolipoproteins Variation

Objective: To study the effects of Apolipoprotein E (ApoE) polymorphism onserum levels of lipids, lipoproteins and apolipoproteins. Methods: Fragments of ApoE gene forthex-on containing codon 112 and 158 polymorphic locus were amplified by PCR, and then digested untilCfo I endonuclease. Genotypes and alleles frequencies of 168 healthy persons in Jiangsu area werecalculated. The effects of ApoE genotypes and alleles on serum lipids, lipoproteins andapolipoproteins variation were analyzed. Results: The effects of ApoE alleles on total cholesterol(TC), law density lipoprotein-cholesterol (LDL-C), ApoB was: along a decreasing gradientε_4>ε_3>ε_2. The effect of ε_4 allele was to increase serum levels of TC, LDL-C and ApoB, andthe ε_2 allele had an effect opposite to that of ε_4 allele. Conclusion: ApoE polymorphism is anindependent genetic factor on individual serum levels of lipids and apolipoproteins.

Herpes simplex virus typeⅠ induces an autophagic response and accelerates the fragmentation of apolipoproteins E protein

OBJECTIVE How infection of Herpes simplex virus typeⅠ(HSV-1) induces enhancement of autophagy.MEHTODS The wild type HSV-1 strain Kos 1.1 was propagated in Vero cells and purified.SK-N-SH cells seeded in DMEM/F12 were exposed to HSV-1 with 6 h or 12 h and multiplicity of infection(MOI) for 10 or 40 in each experiment.The infectious titers of the HSV-1 samples were determined by plaque assays.MDC staining to test the number of autophagosome within the cell after infection with time and moi was indicated in each experiment.At the molecular level,Western blotting and immunofluorescence analyses were done to study the expression of the proteins related to the cell autophagy.The mRNA transcribed from the gene related to autophagy was quantified by reverse transcription followed by real-time PCR.After intranasal infection of different transgenic mice,immunoflurorence studies were done to detected the expression of Aβ42 and proteins related to autophagy from the brain sections.Morris water maze experiment was performed to test the change of spatial learning and memory between different transgenic mice.RESULTS SK-N-SH cell showed time-and moi-dependent increase of MDC positive staining after HSV-1 infection.Western blotting analysis showed that LC3-Ⅱ was less in mock-infected cells but it was detected after 12 h from 10 to 40 moi HSV-1 infected cells.The level increased in a viral concentration-dependent manner.In agreement with the Western blotting results,direct fluorescence microscopy revealed that the signals of LC3 were consistent with their localization on autophagic compartments.P62,another protein related to autophagoysome formation,also increased with MOI.15 ku fragment of intracellular apolipoproteins E(APOE) protein increased after infection,but at the mRNA level it remained the same.The expression of APP showed less decrease but intracellular Aβ42 increased significantly compared with the mock group.Within the brain,after intranasal infection for 7 d,autophagy related proteins LC3 b and P62 increased as well,at the same time Aβ42 was found co-localized with LC3 b within the cell.Behavior test revealed that 17-month-old APOE4 mice had pool spatial learning and memory after infection compared with other groups.CONCLUSION HSV-1 induces an autophagic response and accelerates the fragmentation of APOE protein.

Role of apolipoproteins,ABCA1 and LCAT in the biogenesis of normal and aberrant high density lipoproteins

In this review, we focus on the pathway of biogenesis of HDL, the essential role of apoA-I, ATP binding cassette transporter A1（ABCA1）, and lecithin： cholesterol acyltransferase（LCAT） in the formation of plasma HDL; the generation of aberrant forms of HDL containing mutant apoA-I forms and the role of apoA-IV and apoE in the formation of distinct HDL subpopulations. The biogenesis of HDL requires functional interactions of the ABCA1 with apoA-I（and to a lesser extent with apoE and apoA-IV） and subsequent interactions of the nascent HDL species thus formed with LCAT. Mutations in apoA-I, ABCA1 and LCAT either prevent or impair the formation of HDL and may also affect the functionality of the HDL species formed. Emphasis is placed on three categories of apoA-I mutations. The first category describes a unique bio-engineered apoA-I mutation that disrupts interactions between apoA-I and ABCA1 and generates aberrant prep HDL subpopulations that cannot be converted efficiently to a subpopulations by LCAT. The second category describes natural and bio-engineered apoA-I mutations that generate preβ and small size a4 HDL subpopulations, and are associated with low plasma HDL levels. These phenotypes can be corrected by excess LCAT. The third category describes bio-engineered apoA-I mutations that induce hypertriglyceridemia that can be corrected by excess lipoprotein lipase and also have defective maturation of HDL.The HDL phenotypes described here may serve in the future for diagnosis, prognoses and potential treatment of abnormalities that affect the biogenesis and functionality of HDL.

Progress in the Study of the Correlation between Apolipoproteins and Endometrial Cancer

In recent years, Lipid metabolism disorder has been closely related to malignant tumors. Apolipoprotein (Apo), as an important protein in lipoprotein transport and metabolism, plays an important role in the process of tumor proliferation. Endometrial carcinoma (EC) is a common gynecological malignant tumor, and its incidence is increasing year by year;in which obesity is an independent risk factor for the occurrence and prognosis of EC. This paper discusses the correlation and possible mechanism between different types of Apo and the occurrence, development and prognosis of EC, and briefly reviews the clinical application of some drugs in EC.

Lipids, Lipoproteins and Apolipoproteins Abnormalities inPatients undergoing Dialysis

Twenty hemodialysis (HD) patients and 20 patients on continuous am-bulatory peritoneal dialysis (CAPD) were investigated for lipids, lipoproteins andapolipoproteins abnormalities. HD patients had elevated serum triglyceride, de-creased high-density lipoprotein cholesterol (HDL-C ) and apolipoprotein A-I(Apo A-I ), whi1e CAPD patients had elevated total cho1esterol, triglyceride,low-density lipoprotein cholesterol (LDL-C), Apolipoprotein B (Apo B), Apo B/Apo A-Iratio, and decreased HDL-C, Apo A-I. Because of the molecular sievingeffects of peritoneum, CAPD have a negative effect on these abnormalities. CAPDpatients might be at greater risk of developing coronary artery disease than HD patients who are also at increased riskas compared with normals.

Apolipoproteins and amyloid fibril formation in atherosclerosis

Amyloid fibrils arise from the aggregation of misfolded proteins into highly-ordered structures.The accumulation of these fibrils along with some non-fibrillar constituents within amyloid plaques is associated with the pathogenesis of several human degenerative diseases.A number of plasma apolipoproteins,including apolipoprotein(apo)A-I,apoA-II,apoC-II and apoE are implicated in amyloid formation or influence amyloid formation by other proteins.We review present knowledge of amyloid formation by apolipoproteins in disease,with particular focus on atherosclerosis.Further insights into the molecular mechanisms underlying their amyloidogenic propensity are obtained from in vitro studies which describe factors affecting apolipoprotein amyloid fibril formation and interactions.Additionally,we outline the evidence that amyloid fibril formation by apolipoproteins might play a role in the development and progression of atherosclerosis,and highlight possible molecular mechanisms that could contribute to the pathogenesis of this disease.

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

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.

A multiple-reaction-monitoring mass spectrometric method for simultaneous quantitative analysis of five plasma apolipoproteins

A multiplexed targeted proteomic assay using a mTRAQ-MRM/MS-based approach was developed and assessed to systematically quantify the relative expressions of five candidate plasma apolipoproteins that have been previously shown to be dysregulated in neuropsychiatric disorders and cognitive dysfunction:apolipoprotein H(APOH),apolipoprotein J(APOJ),apolipoprotein A4(APOA4),apolipoprotein E(APOE),and apolipoprotein D(APOD).The peptides and transitions of each APO were carefully selected according to the tandem MS signals acquired on a TripleTOFTM 5600,followed by optimization of the declustering potential and collision energy voltages for transitions on a QTRAP 5500.Our results showed that the collision energies of mTRAQ-labeled peptides were approximately 15%–20%higher than corresponding non-labeled peptides.Through optimized transitions and parameters,we analyzed the relative abundances of the five APOs in human plasma with and without depletion of high abundant proteins.The results indicated that the MRM signals of four target APOs were significantly increased after depletion,while the MRM signal of one APO,APOD,was decreased.Furthermore,the relative abundances of the five target APOs in healthy human plasma were stable,and the ranking of these proteins according to their MS responses changed slightly.Therefore,we deduced that the rank order of the MS signals for these target proteins can be developed as a diagnostic signature for diseased plasma.

Ferroptosis mechanism and Alzheimer's disease

Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.

Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

Isoform-and cell-state-specific APOE homeostasis and function

Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling.It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them.Apolipoprotein E polymorphism,combined with environmental stresses and/or age-related alterations,influences the risk of developing late-onset Alzheimer’s disease.In this review,we discuss our current knowledge of how apolipoprotein E homeostasis,i.e.its synthesis,secretion,degradation,and lipidation,is affected in Alzheimer’s disease.

Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults

Background:Adenosine triphosphatase inhibitory factor 1(IF1)is a key protein involved in energy metabolism.IF1 has been linked to various agerelated diseases,although its relationship with physical activity(PA)remains unclear.Additionally,the apolipoprotein A-I(apoA-I),a PA-modulated lipoprotein,could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase.We examined here the associations between chronic PA and plasma IF1 concentrations among older adults,and we investigated whether apoA-I mediated these associations.Methods:In the present work,1096 healthy adults(63.8%females)aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included.IF1 plasma concentrations(square root of ng/mL)were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial,while PA levels(square root of metabolic equivalent task min/week)were assessed using questionnaires administered each year from baseline to the 3-year visit.Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations.Mediation analyses were conducted to examine whether apoA-I mediated these associations.Mixedeffect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA.Results:Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations(B=0.021;SE=0.010;p=0.043).Mediation analyses revealed that about 37.7%of this relationship was mediated by apoA-I(B_(ab)=0.008;SE=0.004;p=0.023).Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years(time×IF1:B=0.148;SE=0.066;p=0.025).Conclusion:This study demonstrates that regular PA is associated with plasma IF1 concentrations,and it suggests that apoA-I partly mediates this association.Additionally,this study finds that baseline concentrations of IF1 can predict future changes in PA.However,further research is needed to fully understand the mechanisms underlying these observations.

27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression:A key target potentially linking zearalenone and cancer

Zearalenone(ZEN)is a mycotoxin that extensively contaminates food and feed,posing a significant threat to public health.However,the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear.In this study,Sprague-Dawley(SD)rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w.for a duration of 14 days.The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine.Furthermore,ZEN exposure caused a significant reduction in the levels of apolipoprotein E(ApoE)and liver X receptor(LXR)(P<0.05).Conversely,it upregulated the levels of myeloid-derived suppressor cells(MDSCs)markers(P<0.05)and decreased the presence of 27-hydroxycholesterol(27-HC)in the intestine(P<0.05).It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN.Additionally,a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal,breast,and lung cancers.These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine.Notably,ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.

Hepatocyte growth factor enhances the ability of dental pulp stem cells to ameliorate atherosclerosis in apolipoprotein E-knockout mice

BACKGROUND Atherosclerosis(AS),a chronic inflammatory disease of blood vessels,is a major contributor to cardiovascular disease.Dental pulp stem cells(DPSCs)are capable of exerting immunomodulatory and anti-inflammatory effects by secreting cytokines and exosomes and are widely used to treat autoimmune and inflam-mation-related diseases.Hepatocyte growth factor(HGF)is a pleiotropic cytokine that plays a key role in many inflammatory and autoimmune diseases.AIM To modify DPSCs with HGF(DPSC-HGF)and evaluate the therapeutic effect of DPSC-HGF on AS using an apolipoprotein E-knockout(ApoE-/-)mouse model and an in vitro cellular model.METHODS ApoE-/-mice were fed with a high-fat diet(HFD)for 12 wk and injected with DPSC-HGF or Ad-Null modified DPSCs(DPSC-Null)through tail vein at weeks 4,7,and 11,respectively,and the therapeutic efficacy and mechanisms were analyzed by histopathology,flow cytometry,lipid and glucose measurements,real-time reverse transcription polymerase chain reaction(RT-PCR),and enzyme-linked immunosorbent assay at the different time points of the experiment.An in vitro inflammatory cell model was established by using RAW264.7 cells and human aortic endothelial cells(HAOECs),and indirect co-cultured with supernatant of DPSC-Null(DPSC-Null-CM)or DPSC-HGF-CM,and the effect and mechanisms were analyzed by flow cytometry,RT-PCR and western blot.Nuclear factor-κB(NF-κB)activators and inhibitors were also used to validate the related signaling pathways.RESULTS DPSC-Null and DPSC-HGF treatments decreased the area of atherosclerotic plaques and reduced the expression of inflammatory factors,and the percentage of macrophages in the aorta,and DPSC-HGF treatment had more pronounced effects.DPSCs treatment had no effect on serum lipoprotein levels.The FACS results showed that DPSCs treatment reduced the percentages of monocytes,neutrophils,and M1 macrophages in the peripheral blood and spleen.DPSC-Null-CM and DPSC-HGF-CM reduced adhesion molecule expression in tumor necrosis factor-αstimulated HAOECs and regulated M1 polarization and inflammatory factor expression in lipopolysaccharide-induced RAW264.7 cells by inhibiting the NF-κB signaling pathway.CONCLUSION This study suggested that DPSC-HGF could more effectively ameliorate AS in ApoE-/-mice on a HFD,and could be of greater value in stem cell-based treatments for AS.

Apolipoprotein A-IV and its derived peptide, T55−121, improve glycemic control and increase energy expenditure

It is crucial to understand the glucose control within our bodies.Bariatric/metabolic surgeries,including laparoscopic sleeve gastrec-tomy(LSG)and Roux-en-Y gastric bypass(RYGB),provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes(T2D).For the first time,a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics.Apolipoprotein A-IV(apoA-IV)was revealed to be increased dramatically in diabetic obese patients following LSG,and a similar effect was observed in patients after RYGB surgery.Moreover,recombinant apoA-IV protein treatment was proven to enhance insulin secretion in isolated human islets.These results showed that apoA-IV may play a crucial role in gly-cemic control in humans,potentially through enhancing insulin secretion in human islets.ApoA-IV was further shown to enhance energy expenditure and improve glucose tolerance in diabetic rodents,through stimulating glucose-dependent insulin secretion in pancreaticβcells,partially via Gαs-coupled GPCR/cAMP(G protein-coupled receptor/cyclic adenosine monophosphate)signaling.Furthermore,T55-121,truncated peptide 55-121 of apoA-IV,was discovered to mediate the function of apoA-IV.These collective findings contribute to our understanding of the relationship between apoA-IV and glycemic control,highlighting its potential as a biomarker or therapeutic target in managing and improving glucose regulation.

New insights into ATR inhibition in muscle invasive bladder cancer:The role of apolipoprotein B mRNA editing catalytic subunit 3B

Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.

血清前清蛋白、C反应蛋白及载脂蛋白A1对重症肺炎患者预后评估的价值

目的探讨血清前清蛋白(PAB)、C反应蛋白(CRP)及载脂蛋白A1(Apo A1)在评估重症肺炎患者预后中的价值。方法选取63例重症肺炎患者,检测入院后24h内空腹血清PAB、CRP及Apo A1,并计算急性生理学与慢性健康状况评分Ⅱ(APACHEⅡ);按患者APACHEⅡ评分值将患者分为两组(<20分为A组,≥20分为B组),分析两组患者多器官功能障碍综合征(MODS)发生率和病死率。将患者分为MODS组及非MODS组,并根据转归将患者分为存活组和死亡组,比较各组患者的血清PAB、CRP及Apo A1水平的差异。结果 B组MODS发生率和病死率(57.9%,47.4%)均显著高于A组(24.0%,16.0%),差异有统计学意义(P<0.01,P<0.05)。MODS组[(134.13±36.20)mg/L,(0.62±0.21)g/L]及死亡组[(129.05±52.24)mg/L,(0.76±0.29)g/L]PAB、Apo A1分别低于非MODS组[(215.03±72.08)mg/L,(1.06±0.39)g/L]及存活组[(185.52±57.63)mg/L,(1.15±0.36)g/L],差异有统计学意义(P<0.05),而MODS组(102.37±35.65)mg/L及死亡组(96.37±34.72)mg/L CRP分别高于非MODS组(69.68±32.92)mg/L及存活组(62.94±38.36)mg/L(P<0.05)。结论血清PAB、CRP和Apo A1这3种急性时相蛋白对于评估重症肺炎患者病情的危重程度及预后具有一定的价值。

鸡蛋黄低密度脂蛋白理化及加工特性研究进展

鸡蛋黄中的低密度脂蛋白(LDL)是纳米级球形大分子物质,密度为0.982 g/m L,主要存在于卵黄浆质部分,由蛋白质与脂质(中性脂、磷脂和胆固醇)组装而成,脂质是LDL的主要组成成分,占其干重的87%,蛋白质仅占12%。LDL脱脂之后的成分为脱辅基蛋白,通过SDS-PAGE得到鸡蛋黄LDL中5个主要的脱辅基蛋白,相对分子质量分别为15 000、60 000、65 000、80 000和130 000,关于鸡蛋黄LDL中脱辅基蛋白的研究主要集中在其分泌转运方面。目前研究结果表明,这些脱辅基蛋白大部分都是由母鸡血液中极低密度脂蛋白(VLDL)的脱辅基蛋白Apovitellenin I和Apolipoprotein B转运而来。LDL具有较好的乳化活性,也被用于动物精液冷冻保存。将针对LDL的理化性质及加工特性的研究进展展开论述。

Mitochondrial function and regulation of macrophage sterol metabolism and inflammatory responses

The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.

Acupuncture improved lipid metabolism by regulating intestinal absorption in mice

BACKGROUND Non-alcoholic fatty liver disease(NAFLD),in which abnormal lipid metabolism plays an important role in disease progression,has become a pandemic.Abnormal lipid metabolism,for example an increased fat intake,has been thought to be an initial factor leading to NAFLD.The small intestine is the main site of dietary lipid absorption.A number of clinical trials have shown that acupuncture has positive effects in the regulation of lipid metabolism,which is closely associated with the progression of NAFLD.We therefore hypothesized that,acupuncture can improve the conditions of NAFLD by regulating intestinal absorption of lipid.AIM To study the role of acupuncture treatment in the improvement of metabolic syndrome secondary to NAFLD by mouse model.METHODS 8-wk-old male C57BL/6J mice were fed a methionine-and choline-deficient diet for 3 wk.Then,all mice were separated randomly into acupoints group(AG)or non-acupoints group(NG)with high fat diet feeding.Needling treatment was performed at Zu san li,Guan yuan and Yong quan acupoints as acupuncture treatment to AG mice while non-acupoints place to NG mice.Finally,mice were anesthetized with an injection of ketamine-medetomidine and euthanized by exsanguination.RESULTS An apparent improvement of obesity was found in AG mice after acupuncture treatment.In AG mice,the body weight was much lower(22.6±1.2 g vs 28.1±1.0 g,P<0.005)in comparison to NG mice.The length of small intestine in AG mice was significantly shorter(26.7±2.3 cm vs 32.7±2.7 cm,P<0.005).A large amount of chyme was observed in the lumen of the AG small intestine.The expression of microsomal triglyceride transfer protein,apolipoprotein B and apolipoprotein C2 was downregulated.Triacylglycerols(TGs),total cholesterol and nonesterified fatty acid(NEFA)levels of the small intestinal tissue were significantly higher in AG mice,but the serum TGs and NEFA levels were reduced in AG mice.CONCLUSION These results indicate that acupuncture at Zu san li,Guan yuan and Yong quan suppressed lipid absorption by downregulating the expression of apolipoproteins in the small intestine.