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Journal of Lipid Research Dec 1984Plasma lipoprotein metabolism is regulated and controlled by the specific apolipoprotein (apo-) constituents of the various lipoprotein classes. The major... (Review)
Review
Plasma lipoprotein metabolism is regulated and controlled by the specific apolipoprotein (apo-) constituents of the various lipoprotein classes. The major apolipoproteins include apoE, apoB, apoA-I, apoA-II, apoA-IV, apoC-I, apoC-II, and apoC-III. Specific apolipoproteins function in the regulation of lipoprotein metabolism through their involvement in the transport and redistribution of lipids among various cells and tissues, through their role as cofactors for enzymes of lipid metabolism, or through their maintenance of the structure of the lipoprotein particles. The primary structures of most of the apolipoproteins are now known, and various functional domains of these proteins are being mapped using selective chemical modification, synthetic peptides, and monoclonal antibodies. Furthermore, the establishment of structure-function relationships has been greatly advanced by the identification of genetically determined variants of specific apolipoproteins that are associated with a disorder of lipoprotein metabolism. Future studies will rely heavily on the use of recombinant DNA technology and site-specific mutagenesis to elucidate further the correlations between structure and function and the role of specific apolipoproteins in lipoprotein metabolism.
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein C-I; Apolipoprotein C-II; Apolipoprotein C-III; Apolipoproteins; Apolipoproteins A; Apolipoproteins B; Apolipoproteins C; Apolipoproteins E; Cholesterol; Heparin; Humans; Lipolysis; Lipoproteins; Molecular Conformation; Receptors, Cell Surface; Receptors, Lipoprotein
PubMed: 6099394
DOI: No ID Found -
Chinese Medical Journal Nov 2017Parkinson's disease (PD) is featured with motor disorder and nonmotor manifestations including psychological symptoms, autonomic nervous system dysfunction, and... (Review)
Review
OBJECTIVE
Parkinson's disease (PD) is featured with motor disorder and nonmotor manifestations including psychological symptoms, autonomic nervous system dysfunction, and paresthesia, which results in great inconvenience to the patients' life. The apolipoprotein (Apo) superfamily, as a group of potentially modifiable biomarkers in clinical practice, is of increasing significance in the diagnosis, evaluation, and prognosis of PD. The present review summarized the current understanding and emerging findings of the relationship between Apo superfamily and PD.
DATA SOURCES
All literatures were identified by systematically searching PubMed, Embase, and Cochrane electronic databases with terms "Parkinson disease," "apolipoprotein," and their synonyms until May 2017.
STUDY SELECTION
We have thoroughly examined titles and abstracts of all the literatures that met our search strategy and the full text if the research is identified or not so definite. Reference lists of retrieved articles were also scrutinized for additional relevant studies.
RESULTS
The levels of plasma ApoA1 are inversely correlated with the risk of PD and the lower levels of ApoA1 trend toward association with poorer motor performance. Higher ApoD expression in neurons represents more puissant protection against PD, which is critical in delaying the neurodegeneration process of PD. It is suggested that APOE alleles are related to development and progression of cognitive decline and age of PD onset, but conclusions are not completely identical, which may be attributed to different ApoE isoforms. APOJ gene expressions are upregulated in PD patients and it is possible that high ApoJ level is an indicator of PD dementia and correlates with specific phenotypic variations in PD.
CONCLUSIONS
The Apo superfamily has been proved to be closely involved in the initiation, progression, and prognosis of PD. Apos and their genes are of great value in predicting the susceptibility of PD and hopeful to become the target of medical intervention to prevent the onset of PD or slow down the progress. Therefore, further large-scale studies are warranted to elucidate the precise mechanisms of Apos in PD.
Topics: Apolipoprotein A-I; Apolipoproteins; Dementia; Female; Humans; Male; Parkinson Disease
PubMed: 29067960
DOI: 10.4103/0366-6999.217092 -
International Journal of Molecular... Aug 2022A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and... (Review)
Review
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer's disease. The human gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.
Topics: Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Atherosclerosis; Cardiovascular Diseases; Humans; Mice; Receptors, LDL
PubMed: 36077289
DOI: 10.3390/ijms23179892 -
Journal of the American Society of... May 2023
Topics: Apolipoprotein L1; Phenotype; Genotype; Apolipoproteins
PubMed: 37126670
DOI: 10.1681/ASN.0000000000000123 -
Cancer Research Sep 2023The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of...
UNLABELLED
The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The APOE germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease.
SIGNIFICANCE
APOE germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis-promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes.
Topics: Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Carrier Proteins; Melanoma
PubMed: 37335131
DOI: 10.1158/0008-5472.CAN-23-1252 -
Atherosclerosis Oct 2021Apolipoprotein M (apoM) is a member of the lipocalin superfamily and is predominantly associated with high-density lipoprotein (HDL). It was found that apoM is the... (Review)
Review
Apolipoprotein M (apoM) is a member of the lipocalin superfamily and is predominantly associated with high-density lipoprotein (HDL). It was found that apoM is the chaperon to the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Several studies have since contributed to expand the knowledge on apoM, S1P, and the apoM/S1P-complex in cardiovascular diseases. For instance, the HDL-bound apoM/S1P complex serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. Evidence indicates, however, that the apoM/S1P complex may has both protective and harmful effects on the cardiovascular system, which suggests the need for more research to understand the interplay between these molecules. This review aims to shed light on the most recent findings on apoM/S1P-signaling and its impact on endothelial dysfunction, inflammation, and cardiovascular diseases. Finally, it will be discussed whether drugs that target apoM and/or S1P-signaling may be beneficial to patients with cardiovascular and inflammatory diseases.
Topics: Apolipoproteins; Apolipoproteins M; Cardiovascular System; Endothelial Cells; Humans; Inflammation; Lysophospholipids; Sphingosine
PubMed: 34482091
DOI: 10.1016/j.atherosclerosis.2021.08.039 -
Proceedings of the National Academy of... Feb 2023The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart...
The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein.
Topics: Apolipoprotein E4; Apolipoprotein E3; Apolipoprotein E2; Apolipoproteins E; Protein Conformation; Protein Isoforms
PubMed: 36749730
DOI: 10.1073/pnas.2215371120 -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405 -
Current Opinion in Lipidology Aug 2022A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or... (Review)
Review
PURPOSE OF REVIEW
A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or posttranslational modifications (PTMs) in specific locations on the amino acid backbone. Apolipoproteins A1 and A2 are highly abundant apolipoproteins that mediate HDL structure and function. ApoA1 and apoA2 are known to undergo PTMs, which results in multiple proteoforms. However, the catalogue of apoA1 and apoA2 proteoforms as well as their associations with cardiometabolic health characteristics has not been described until recently. In this brief review, we discuss recent efforts to catalogue the spectrum of apoA1 and apoA2 proteoforms, to understand the relationships between the relative abundance of these proteoforms with cardiometabolic phenotypic characteristics, and we will discuss the implications of these findings to future research.
RECENT FINDINGS
A broad spectrum of apoA1 and apoA2 proteoforms has been characterized. Although, the types of apoA1 and A2 proteoforms are consistent across individuals, the relative abundances of proteoforms can vary substantially between individuals. Proteoform-specific associations with cardiometabolic characteristics in humans, independent of absolute apolipoprotein abundance, have been described. These recent findings suggest multiple levels of protein structural variation that arise from known and unknown metabolic pathways may be important markers or mediators of cardiometabolic health.
SUMMARY
Understanding the associations between apolipoprotein proteoforms and phenotype may lead to enhanced understanding of how apolipoproteins mediate lipid metabolism and affect atherosclerotic cardiovascular disease (ASCVD) risk, which may lead to discovery of novel markers of risk and/or key mechanistic insights that may drive further druggable targets for modifying lipid metabolism and reducing ASCVD risk.
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Atherosclerosis; Humans; Protein Processing, Post-Translational
PubMed: 36082946
DOI: 10.1097/MOL.0000000000000840 -
Archives of Razi Institute Feb 2022Neurodegenerative disorders are those which affect cognitive functions. Misfolding of proteins especially apolipoprotein E is a key genetic factor involved in several... (Review)
Review
Neurodegenerative disorders are those which affect cognitive functions. Misfolding of proteins especially apolipoprotein E is a key genetic factor involved in several cognitive impairments. Increasing evidence also described the toxic effects of metals, generated by both nature and humans, on the development of neurological disorders. Understanding of interaction between toxic metals and apolipoprotein E protein in cognitive decline diosrders would provide alternative treatment options. Google Scholar and PubMed database were used to search the articles using different search terms like 'toxic metals', 'cognitive decline', 'Apolipoprotein E', "neurodegenerative disorders" and "metals neurotoxicity". Only those papers were included that discussed the metal exposure-apolipoprotein association in the development of cognitive decline disorders. Heavy metals are particularly recognized as a major source of neurotoxicity. These toxic metals can interact with genetic factors and play important role in disease etiology. Understanding the underlying mechanism of this interaction could provide tremendous benefits to treat cognitive decline disorders. In this study, the role of the apolipoprotein E4 gene in the development of cognitive disease conditions and their phenotypes has been discussed thoroughly which leads to the accumulation of amyloid-beta fibrils. This exploratory study revealed novel hypothetical findings which might contribute to the understanding of the neurotoxic effects of chronic toxic metals exposure and possibly improve our knowledge on the molecular mechanisms linking metal exposure to cognitive decline disorder risk.
Topics: Humans; Apolipoprotein E4; Apolipoproteins E; Cognition; Neurodegenerative Diseases
PubMed: 35891722
DOI: 10.22092/ARI.2021.356078.1771