ATP-binding Cassette Transporter A1 Involves In Diabetes Associated Cognitive Impairment By Mediating Cholesterol Metabolism

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Interactions among lipid profile,ABCA1 R219 K polymorphism,and mild cognitive impairment in type 2 diabetes mellitusBackground: Accumulate evidences suggested that adverse lipid changes are risk factors not only for type 2 diabetes mellitus(T2DM)but also for neurodegenerative disorders.The ATP-binding cassette A1 transporter(ABCA1)gene contributes to both lipid processing and amyloid-?(A?)may be a promising biological target during pathology of cognitive impairment in T2 DM.Objectives:This study aims to explore interactions among lipids,ABCA1 R219 K polymorphism,and cognitive function in T2 DM,and to investigate the predict value of ABCA1 R219 K polymorphism for mild cognitive impairment(MCI)in T2 DM patients.Methods: This is a case-control study,which enrolled 226 T2 DM patients.According to Montreal Cognitive Assessment(MoCA)scoring system,the included patients were assigned to MCI or cognitive-healthy groups.Clinical parameters including blood pressure,blood glucose,glycosylated hemoglobin,and lipids were collected;testing scores of different cognitive domains were recorded.ABCA1 R219 K variants were analyzed by polymerase chain reaction-restriction fragment length polymorphism.The statistical analyses were conducted by SPSS 20.0.Results: 1.T2 DM with MCI showed all cognitive domains decline and exhibited lower serum high-density lipoprotein(HDL-c),apolipoprotein A1(apoA-I)levels and higher total cholesterol level than controls.2.Education years(r = 0.474,P < 0.001;r = 0.471,P < 0.001),HDL-c(r = 0.143,P = 0.043;r = 0.301,P = 0.001)and apoA-I(r = 0.146,P = 0.039;r = 0.230,P = 0.016)were positively correlated with MoCA score,whereas age was inversely associated with MoCA score(r =-0.253;P < 0.001;r =-0.208;P = 0.020)in all people and MCI group,separately.3.The stratification analyses revealed that subjects with higher HDL-c showed better attention,memory for verbal,visual,and logical functions than lower HDL-c group(P < 0.05).4.No significant differences were observed among distributions of ABCA1 R219 K variants between MCI and control group.5.In MCI individuals,the apoA-I level increased in ascending order during RR,RK,KK genotypes.Statistically difference was found between RR and KK genotypes.The increased tendency of HDL-c level was also displayed in ascending order according to RR,RK,KK genotypes,but no statistical difference(P = 0.055).Conclusion: This study suggests that R219 K genotype may have an effect on HDL-c levels and serum HDL-c level may have a positive influence on cognition,especially memory function in T2 DM.However,The polymorphism of ABCA1 R219 K gene was not found to be significantly different between MCI and cognitive normal population in T2 DM.It is necessary to further expand the sample size to determine whether the ABCA1 genotype contribute to dyslipidemia,further influence the cognition in T2 DM.Part ? Activation of LXR-? improves cognitive function of KKAy mice through ABCA1Background: The disorder of cholesterol metabolism is the common pathological basis of type 2 diabetes and alzheimer's disease,and may be associated with the occurrence of cognitive dysfunction in diabetes.Liver X receptor(LXR)is an oxidized steroid-activated nuclear receptor that regulates intracellular cholesterol levels by regulating genes involved in cholesterol transport,such as ABCA1.LXR agonists can activate LXR-?,regulate cholesterol efflux and decrease A? levels through upregulate ABCA1 gene expression.ABCA1 levels in diabetic patients decrease significantly,looking for effective methods to up-regulate the expression of ABCA1 may be a new target for the prevention and treatment of diabetic cognitive dysfunction.Objectives:To observe whether LXR-? agonist improves cognitive function of KKAy mice by regulating ABCA1 protein and its effect on A? metabolism.Methods:This study used KKAy mice as the animal model of cognitive dysfunction of T2 DM.Different doses of T0901317 were applied to KKAy mice as prevention or treatment method.The prevention group were given T0901317 at the age of 9 week;the treatment group received daily administration of T0901317 at the age of 15 week.The experiments of dark-avoidance test and the Morris water maze test were used to detect the behavioral changes of mice.The morphological changes in brain tissue of mice were detected by HE and Nissl staining.Immunohistochemistry was used to detect the expression of LXR-?,ABCA1 and A?42 in hippocampus.RT-PCR and Western Blot were used to determine the m RNA and protein expression levels of LXR-? and ABCA1 in hippocampus of KKAy mice.Results: 1.The body weight,fasting blood glucose(FBG),total cholesterol(TC)and high-density lipoprotein(FBG)levels of KKAy mice were significantly higher than those of control mice of the same age group;T0901317 had no influence on the body weight of mice.Compared with the diabetic model group,FBG and TC in T0901317 prevention or treatment group were decreased,while HDL levels increased.2.In the dark-avoidance experiment,compared to the control group,mice in the model group showed shorter dark-avoidance latency and increased number of errors than the control group.In the water maze test,the latency period of the model group was prolonged;while the number of crossing the platform and the target quadrant residence time were all reduced.After prevention or treatment of T0901317,the learning and memory functions were significantly improved in KKAy mice.3.Compared to the control group,the structure of neurons in hippocampus of T0901317 intervention groups were improved to some extent.Neuron morphology damage in the intervention groups were reduced,and the Nissl bodies were increased.4.Immunohistochemical staining results showed that the IOD values of LXR-? and ABCAl in model group were significantly decreased compared with those in control group;and the A?42 staining was deeper,but no statistical significant.After T0901317 prevention or treatment,the expression of LXR-? and ABCA1 increased,and the amount of A?42 was significantly reduced.5.The expression of LXR-? and ABCA1 at m RNA and protein levels were significantly decreased in diabetic model group than those in control group.The prevention and treatment groups all showed higher m RNA and protein levels of LXR-? and ABCA1 than the model group.Conclusion: ABCA1 is involved in the pathogenesis of cognitive impairment in diabetes,which may have a protective effect on cognitive function.LXR-? agonist may improve diabetes associated cognitive dysfunction by increasing ABCA1 levels and decreasing A? deposition.Part ? LXR-? activation regulates A? metabolism in PC12 cells by enhancing the expression of ABCA1Background: A? metabolism is closely associated with the occurrence and development of cognitive impairment in T2 DM.Our previous results demonstrated that LXR-? agonist can improve the learning and memory functions of KKAy mice by up-regulating ABCA1 expression and decreasing A? production.However,the mechanism of LXR-? agonist reducing A? and improving cognitive function in diabetic status is not clear.Objectives:To observe the effect of T0901317 on cholesterol and A? metabolism in PC12 cells cultured in high glucose(HG),and to explore whether T0901317 could regulate A? metabolism by promoting the intracellular cholesterol efflux through the ABCA1 cholesterol transport system and to elucidate its possible mechanism.Methods:PC12 cells induced by nerve growth factor were treated with HG and T0901317 for intervention.The cholesterol concentration in cell culture medium was detected by kit,and intracellular cholesterol efflux was calculated.The level of A?42 was detected by enzyme-linked immunosorbent assay(ELISA).RT-PCR and Western Blot were used to detect m RNA and protein expression of LXR-?,ABCA1,APP,ADAM10 and BACE1.The effects of ABCA1 cholesterol transport system on A? metabolism were observed after LXR-? and ABCA1 were inhibited by LXR-? si RNA and ABCA1 si RNA.Results: 1.Compared with the normal control group,m RNA and protein levels of LXR-?,ABCA1 and ADAM10 were decreased in HG group,m RNA and protein levels of APP and BACE1 significantly increased,cholesterol efflux decreased and the A?42 production increased.Compared to HG group,m RNA and protein levels of LXR-? and ABCA1 were significantly increased after T0901317 intervention,BACE1 protein expression decreased,cholesterol efflux increased,and A?42 level decreased.2.After LXR-? si RNA inhibited the expression of LXR-?,the up-regulated effects of T0901317 on LXR-? and ABCA1 protein significantly reduced;the effects of T0901317 promoting intracellular cholesterol efflux and the lowering effects on BACE1 protein expression and A? production were significantly inhibited.3.After using ABCA1 si RNA to suppress ABCA1 expression in PC12 cells,LXR-? m RNA and protein levels were not changed;however,the increasing effects of T0901317 on ABCA1 protein expression decreased;the effects of T0901317 promoting intracellular cholesterol efflux,reducing BACE1 protein and A?42 production in PC12 cells were also significantly inhibited.Conclusion: ABCA1-mediated cholesterol metabolism participates in the occurrence of cognitive impairment in diabetes.T0901317 can up-regulate ABCA1 expression in PC12 cells damaged by HG,increase cellular cholesterol efflux,decrease BACE1 protein level and A? production.After LXR-? si RNA or ABCA1 si RNA was used,the effects of T0901317 on increasing ABCA1 expression,promoting intracellular cholesterol efflux,decreasing BACE1 protein and A? production are inhibited.It is shown that LXR-? activation may influence cholesterol levels through ABCA1,then reduce BACE1 protein expression and regulate A? metabolism in high glucose circumstance.