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Lipids in Health and Disease Jul 2022Clinical investigations have found that there was a close association between T2DM and adverse cardiovascular events, with possible mechanisms included inflammation,...
BACKGROUND
Clinical investigations have found that there was a close association between T2DM and adverse cardiovascular events, with possible mechanisms included inflammation, apoptosis, and lipid metabolism disorders. High serum GDF-15 concentration and the apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) are involved in the above-mentioned mechanisms and are thought to be related to the occurrence of adverse cardiovascular events. However, it remains unclear whether circulating GDF-15 levels and the ApoB/ApoA1 ratio are related to T2DM patients with CAD.
METHODS
T2DM patients with or without CAD were eligible for this study. According to the inclusion and exclusion criteria, 502 T2DM patients were enrolled between January 2021 and December 2021 and were then divided into T2DM group (n = 249) and CAD group (n = 253). The ApoB, ApoA1 and GDF-15 concentrations were measured at hospital admission and the ApoB/ApoA1 ratio was then calculated.
RESULTS
Compared with T2DM group, serum GDF-15 levels and ApoB/ApoA1 ratio increased in CAD group. Furthermore, a positive relationship between the occurrence of CAD in diabetic population and circulating GDF-15 concentrations and ApoB/ApoA1 ratio was observed in logistic regression analysis (p < 0.01). Restrictive cubic spline analysis after adjusted for multiple risky variables showed that serum GDF-15 or ApoB/ApoA1 ratio correlated positively with CAD.
CONCLUSIONS
Circulating GDF-15 levels and serum ApoB/ApoA1 ratio vary in CAD group and T2DM group. ApoB/ApoA1 and GDF-15 may be helpful for predicting the occurrence of CAD in patients with T2DM.
Topics: Apolipoprotein A-I; Apolipoprotein B-100; Apolipoproteins B; Biomarkers; Coronary Artery Disease; Diabetes Mellitus, Type 2; Growth Differentiation Factor 15; Humans
PubMed: 35842724
DOI: 10.1186/s12944-022-01667-1 -
Comparative Biochemistry and... Feb 2010Apolipoproteins are the protein components of lipoproteins that have the innate ability to inter convert between a lipid-free and a lipid-bound form in a facile manner,... (Review)
Review
Apolipoproteins are the protein components of lipoproteins that have the innate ability to inter convert between a lipid-free and a lipid-bound form in a facile manner, a remarkable property conferred by the helix bundle motif. Composed of a series of four or five amphipathic alpha-helices that fold to form a helix bundle, this motif allows the en face orientation of the hydrophobic faces of the alpha-helices in the protein interior in the lipid-free state. A conformational switch then permits helix-helix interactions to be substituted by helix-lipid interactions upon lipid binding interaction. This review compares the apolipoprotein high-resolution structures and the factors that trigger this switch in insect apolipophorin III and the mammalian apolipoproteins, apolipoprotein E and apolipoprotein A-I, pointing out the commonalities and key differences in the mode of lipid interaction. Further insights into the lipid-bound conformation of apolipoproteins are required to fully understand their functional role under physiological conditions.
Topics: Animals; Apolipoproteins; Humans; Lipid Metabolism; Lipids; Models, Molecular; Protein Binding; Protein Conformation; Protein Folding; Protein Structure, Secondary
PubMed: 19770066
DOI: 10.1016/j.cbpa.2009.09.009 -
Molecular Neurodegeneration Nov 2022Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases....
BACKGROUND
Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear.
METHODS
To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination.
RESULTS
We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice.
CONCLUSIONS
Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.
Topics: Animals; Mice; Apolipoprotein E2; Apolipoprotein E4; Microglia; Apolipoprotein E3; Lipid Metabolism; Cuprizone; Apolipoproteins E; Demyelinating Diseases
PubMed: 36419137
DOI: 10.1186/s13024-022-00577-1 -
Journal of Lipid Research May 2018Circulating apolipoprotein-defined lipoprotein subclasses (ADLS) and apolipoproteins predict vascular events in the general and type 2 diabetes populations, but data in...
Circulating apolipoprotein-defined lipoprotein subclasses (ADLS) and apolipoproteins predict vascular events in the general and type 2 diabetes populations, but data in T1D are limited. We examined associations of ADLS, serum apolipoproteins, and conventional lipids with carotid intima-media thickness (IMT) measured contemporaneously and 6 years later in 417 T1D participants [men: n = 269, age 42 ± 6 y (mean ± SD); women: n = 148, age 39 ± 8 y] in the Epidemiology of Diabetes Interventions and Complications study, the follow-up of the Diabetes Control and Complications Trial (DCCT). Date were analyzed by multiple linear regression stratified by sex, and adjusted for time-averaged hemoglobin A1C, diabetes duration, hypertension, BMI, albuminuria, DCCT randomization, smoking, statin treatment, and ultrasound devices. In cross-sectional analyses, lipoprotein B (Lp-B), Lp-B:C, Lp-B:E+Lp-B:C:E, Apo-A-II, Apo-B, Apo-C-III-HP (heparin precipitate; i.e., Apo-C-III in Apo-B-containing lipoproteins), and Apo-E were positively associated with common and/or internal carotid IMT in men, but only Apo-C-III (total) was (positively) associated with internal carotid IMT in women. In prospective analyses, Lp-B, Apo-B, and Apo-C-III-HP were positively associated with common and/or internal carotid IMT in men, while Lp-A1:AII and Apo-A1 were inversely associated with internal carotid IMT in women. The only significant prospective association between conventional lipids and IMT was between triacylglycerols and internal carotid IMT in men. ADLS and apolipoprotein concentrations may provide sex-specific biomarkers and suggest mechanisms for IMT in people with T1D.
Topics: Adult; Apolipoproteins; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Male; Regression Analysis
PubMed: 29576550
DOI: 10.1194/jlr.P080143 -
Circulation. Genomic and Precision... Jun 2018
Topics: Adult; Black or African American; Apolipoprotein L1; Apolipoproteins; Cardiovascular Diseases; Humans; Kidney Diseases
PubMed: 29899046
DOI: 10.1161/CIRCGEN.118.002212 -
International Journal of Molecular... Dec 2023The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm... (Review)
Review
The circadian rhythm is a 24 h internal clock within the body that regulates various factors, including sleep, body temperature, and hormone secretion. Circadian rhythm disruption is an important risk factor for many diseases including neurodegenerative illnesses. The central and peripheral oscillators' circadian clock network controls the circadian rhythm in mammals. The clock genes govern the central clock in the suprachiasmatic nucleus (SCN) of the brain. One function of the circadian clock is regulating lipid metabolism. However, investigations of the circadian regulation of lipid metabolism-associated apolipoprotein genes in the brain are lacking. This review summarizes the rhythmic expression of clock genes and lipid metabolism-associated apolipoprotein genes within the SCN in . Nine of the twenty apolipoprotein genes identified from searching the published database (SCNseq and CircaDB) are highly expressed in the SCN. Most apolipoprotein genes (ApoE, ApoC1, apoA1, ApoH, ApoM, and Cln) show rhythmic expression in the brain in mice and thus might be regulated by the master clock. Therefore, this review summarizes studies on lipid-associated apolipoprotein genes in the SCN and other brain locations, to understand how apolipoproteins associated with perturbed cerebral lipid metabolism cause multiple brain diseases and disorders. This review describes recent advancements in research, explores current questions, and identifies directions for future research.
Topics: Mice; Animals; Lipid Metabolism; Brain; Circadian Rhythm; Suprachiasmatic Nucleus; Circadian Clocks; Apolipoproteins; Mammals
PubMed: 38139244
DOI: 10.3390/ijms242417415 -
Journal of Cellular and Molecular... Jan 2022In normal pregnancy, hepatic metabolism adaptation occurs with an increase in lipid biosynthesis. Placental shedding of syncytiotrophoblast-derived extracellular...
In normal pregnancy, hepatic metabolism adaptation occurs with an increase in lipid biosynthesis. Placental shedding of syncytiotrophoblast-derived extracellular vesicles (STBEVs) into the maternal circulation constitutes a major signalling mechanism between foetus and mother. We investigated whether STBEVs from normal pregnant women might target liver cells in vitro and induce changes in lipid synthesis. This study was performed at the Nuffield Department of Women's & Reproductive Health, Oxford, UK. STBEVs were obtained by dual-lobe placental perfusion from 11 normal pregnancies at term. Medium/large and small STBEVs were collected by ultracentrifugation at 10,000g and 150,000g, respectively. STBEVs were analysed by Western blot analysis and flow cytometry for co-expression of apolipoprotein-E (apoE) and placental alkaline phosphatase (PLAP). The uptake of STBEVs by liver cells and the effect on lipid metabolism was evaluated using a hepatocarcinoma cell line (HepG2 cells). Data were analysed by one-way ANOVA and Student's t test. We demonstrated that: (a) STBEVs carry apoE; (b) HepG2 cells take up STBEVs through an apoE-LDL receptor interaction; (c) STBEV incorporation into HepG2 cells resulted in (i) increased cholesterol release (ELISA); (ii) increased expression of the genes SQLE and FDPS (microarray) involved in cholesterol biosynthesis; (iii) downregulation of the CLOCK gene (microarray and PCR), involved in the circadian negative control of lipid synthesis in liver cells. In conclusion, the placenta may orchestrate the metabolic adaptation of the maternal liver through release of apoE-positive STBEVs, by increasing lipid synthesis in a circadian-independent fashion, meeting the nutritional needs of the growing foetus.
Topics: Apolipoproteins; Apolipoproteins E; Extracellular Vesicles; Female; Humans; Lipids; Liver; Placenta; Pregnancy; Trophoblasts
PubMed: 34894055
DOI: 10.1111/jcmm.17056 -
Inhalation Toxicology 2023Environmental exposures exacerbate age-related pathologies, such as cardiovascular and neurodegenerative diseases. Nanoparticulates, and specifically carbon...
Aging influence on pulmonary and systemic inflammation and neural metabolomics arising from pulmonary multi-walled carbon nanotube exposure in apolipoprotein E-deficient and C57BL/6 female mice.
OBJECTIVE
Environmental exposures exacerbate age-related pathologies, such as cardiovascular and neurodegenerative diseases. Nanoparticulates, and specifically carbon nanomaterials, are a fast-growing contributor to the category of inhalable pollutants, whose risks to health are only now being unraveled. The current study assessed the exacerbating effect of age on multiwalled-carbon nanotube (MWCNT) exposure in young and old C57BL/6 and ApoE mice.
MATERIALS AND METHODS
Female C57BL/6 and apolipoprotein E-deficient (ApoE) mice, aged 8 weeks and 15 months, were exposed to 0 or 40 µg MWCNT via oropharyngeal aspiration. Pulmonary inflammation, inflammatory bioactivity of serum, and neurometabolic changes were assessed at 24 h post-exposure.
RESULTS
Pulmonary neutrophil infiltration was induced by MWCNT in bronchoalveolar lavage fluid in both C57BL/6 and ApoE. Macrophage counts decreased with MWCNT exposure in ApoE mice but were unaffected by exposure in C57BL/6 mice. Older mice appeared to have greater MWCNT-induced total protein in lavage fluid. BALF cytokines and chemokines were elevated with MWCNT exposure, but CCL2, CXCL1, and CXCL10 showed reduced responses to MWCNT in older mice. However, no significant serum inflammatory bioactivity was detected. Cerebellar metabolic changes in response to MWCNT were modest, but age and strain significantly influenced metabolite profiles assessed. ApoE mice and older mice exhibited less robust metabolite changes in response to exposure, suggesting a reduced health reserve.
CONCLUSIONS
Age influences the pulmonary and neurological responses to short-term MWCNT exposure. However, with only the model of moderate aging (15 months) in this study, the responses appeared modest compared to inhaled toxicant impacts in more advanced aging models.
Topics: Female; Animals; Mice; Nanotubes, Carbon; Mice, Inbred C57BL; Lung; Bronchoalveolar Lavage Fluid; Inflammation; Apolipoproteins E; Apolipoproteins; Inhalation Exposure
PubMed: 35037817
DOI: 10.1080/08958378.2022.2026538 -
Arteriosclerosis, Thrombosis, and... Sep 2017
Topics: Black or African American; Apolipoprotein L1; Apolipoproteins; Cardiovascular Diseases; Humans; Hypertension; Kidney Diseases
PubMed: 28835482
DOI: 10.1161/ATVBAHA.117.309756 -
The FEBS Journal Dec 2019Although the interaction of apoE isoforms with amyloid-β (Aβ) peptides plays a critical role in the progression of Alzheimer's disease, how they interact with each...
Although the interaction of apoE isoforms with amyloid-β (Aβ) peptides plays a critical role in the progression of Alzheimer's disease, how they interact with each other remains poorly understood. Here, we investigate the molecular mechanism of apoE-Aβ interactions by comparing the effects of the different domains of apoE on Aβ. The kinetics of aggregation of Aβ1-42 are delayed dramatically in the presence of substoichiometric, nanomolar concentrations of N-terminal fragment (NTF), C-terminal fragment (CTF) and full-length apoE both in lipid-free and in lipidated forms. However, interactions between apoE and Aβ as measured by intermolecular Förster resonance energy transfer (FRET) analysis were found to be minimal at t = 0 but to increase in a time-dependent manner. Thus, apoE must interact with one or more 'intermediates' rather than the monomers of Aβ. Kinetics of FRET between full-length apoE4 labelled with EDANS at position 62 or 139 or 210 or 247 or 276, and tetramethylrhodamine-labelled Aβ (TMR-Aβ), further support an involvement of all the three domains of apoE in the interactions. However, the above-mentioned residues do not appear to form a single pocket in the 3-dimensional structure of apoE. A competitive binding assay examining the effects of unlabelled fragments or full-length apoE on the FRET between EDANS-apoE and TMR-Aβ show that binding affinity of the full-length apoE to Aβ is much higher than that of the fragments. Furthermore, apoE4 is found to interact more strongly than apoE3. We hypothesize that high affinity of the apoE-Aβ interaction is attained due to multivalent binding mediated by multiple interactions between oligomeric Aβ and full-length apoE.
Topics: Amyloid beta-Peptides; Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Fluorescence Resonance Energy Transfer; Humans; Kinetics; Peptide Fragments; Protein Binding
PubMed: 31287614
DOI: 10.1111/febs.14988