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Cells Mar 2021Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide... (Review)
Review
Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.
Topics: Apolipoprotein A-I; Apolipoproteins; Cardiovascular Diseases; Humans; Peptides
PubMed: 33800446
DOI: 10.3390/cells10030597 -
Cell Reports Dec 2023Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A....
Apolipoproteins L1 and L3 (APOLs) are associated at the Golgi with the membrane fission factors phosphatidylinositol 4-kinase-IIIB (PI4KB) and non-muscular myosin 2A. Either APOL1 C-terminal truncation (APOL1Δ) or APOL3 deletion (APOL3-KO [knockout]) reduces PI4KB activity and triggers actomyosin reorganization. We report that APOL3, but not APOL1, controls PI4KB activity through interaction with PI4KB and neuronal calcium sensor-1 or calneuron-1. Both APOLs are present in Golgi-derived autophagy-related protein 9A vesicles, which are involved in PI4KB trafficking. Like APOL3-KO, APOL1Δ induces PI4KB dissociation from APOL3, linked to reduction of mitophagy flux and production of mitochondrial reactive oxygen species. APOL1 and APOL3, respectively, can interact with the mitophagy receptor prohibitin-2 and the mitophagosome membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). While APOL1 conditions PI4KB and APOL3 involvement in mitochondrion fission and mitophagy, APOL3-VAMP8 interaction promotes fusion between mitophagosomal and endolysosomal membranes. We propose that APOL3 controls mitochondrial membrane dynamics through interactions with the fission factor PI4KB and the fusion factor VAMP8.
Topics: Apolipoprotein L1; Mitochondrial Membranes; Golgi Apparatus; Mitochondria; 1-Phosphatidylinositol 4-Kinase; Apolipoproteins; Mitochondrial Dynamics
PubMed: 38041817
DOI: 10.1016/j.celrep.2023.113528 -
Nutrients Jun 2022Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system....
Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8−12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.
Topics: Apolipoprotein B-100; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Cardiovascular Diseases; Cognitive Dysfunction; Humans; Mass Spectrometry; Protein Isoforms
PubMed: 35745204
DOI: 10.3390/nu14122474 -
The European Journal of Neuroscience Nov 2022The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a... (Review)
Review
The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease-related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi-hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi-hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE-centric literature.
Topics: Humans; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E
PubMed: 35510513
DOI: 10.1111/ejn.15685 -
Clinical Chemistry Feb 2005
Topics: Apolipoprotein A-V; Apolipoprotein C-II; Apolipoprotein C-III; Apolipoproteins; Apolipoproteins A; Apolipoproteins C; Humans; Hypertriglyceridemia; Lipoprotein Lipase; Lipoproteins, HDL; Lipoproteins, LDL; Triglycerides
PubMed: 15681559
DOI: 10.1373/clinchem.2004.044826 -
Journal of the American Society of... Apr 2017
Topics: Apolipoprotein L1; Apolipoproteins; Cell Death; Genetic Predisposition to Disease; Humans; Hypertrophy; Lipoproteins, HDL
PubMed: 28196842
DOI: 10.1681/ASN.2016111262 -
International Journal of Molecular... Nov 2022High-density lipoprotein (HDL)-bound apolipoprotein M/sphingosine 1-phosphate (ApoM/S1P) complex in cardiovascular diseases serves as a bridge between HDL and...
High-density lipoprotein (HDL)-bound apolipoprotein M/sphingosine 1-phosphate (ApoM/S1P) complex in cardiovascular diseases serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. To date, S1P and ApoM in patients with untreated heterozygous familial hypercholesterolemia (HeFH) have not been extensively studied. Eighty-one untreated patients with HeFH and 32 healthy control subjects were included in this study. Serum S1P, ApoM, sCD40L, sICAM-1, sVCAM-1, oxLDL, and TNFα concentrations were determined by ELISA. PON1 activities were measured spectrophotometrically. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Significantly higher serum S1P and ApoM levels were found in HeFH patients compared to controls. S1P negatively correlated with large HDL and positively with small HDL subfractions in HeFH patients and the whole study population. S1P showed significant positive correlations with sCD40L and MMP-9 levels and PON1 arylesterase activity, while we found significant negative correlation between sVCAM-1 and S1P in HeFH patients. A backward stepwise multiple regression analysis showed that the best predictors of serum S1P were large HDL subfraction and arylesterase activity. Higher S1P and ApoM levels and their correlations with HDL subfractions and inflammatory markers in HeFH patients implied their possible role in endothelial protection.
Topics: Humans; Apolipoproteins M; Endothelial Cells; Apolipoproteins; Biomarkers; Hyperlipoproteinemia Type II; Aryldialkylphosphatase
PubMed: 36430543
DOI: 10.3390/ijms232214065 -
BMC Genomic Data Apr 2021Hyperlipidemia plays an important role in the etiology of cardio-cerebrovascular disease. Over recent years, a number of studies have explored the impact of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hyperlipidemia plays an important role in the etiology of cardio-cerebrovascular disease. Over recent years, a number of studies have explored the impact of apolipoprotein genetic polymorphisms in hyperlipidemia, but considerable differences and uncertainty have been found in their association with different populations from different regions.
RESULTS
A total of 59 articles were included, containing in total 13,843 hyperlipidemia patients in the case group and 15,398 healthy controls in the control group. Meta-analysis of the data indicated that APOA5-1131 T > C, APOA1 -75 bp, APOB XbaI, and APOE gene polymorphisms were significantly associated with hyperlipidemia, with OR values of 1.996, 1.228, 1.444, and 1.710, respectively. All P-values were less than 0.05.
CONCLUSIONS
Meta-analysis of the data indicated that the C allele of APOA5 1131 T > C, the A allele at APOA1-75 bp, the APOB XbaI T allele, and the ε2 and ε4 allele of APOE were each a risk factor for susceptibility for hyperlipidemia.
Topics: Adult; Aged; Apolipoproteins; Apolipoproteins B; Apolipoproteins E; Female; Humans; Hyperlipidemias; Male; Middle Aged; Polymorphism, Genetic
PubMed: 33836655
DOI: 10.1186/s12863-021-00968-1 -
Physiological Research 2000Apolipoprotein E (apoE) is a plasma lipoprotein which plays a basic role in the degradation of particles rich in cholesterol and triglycerides. It is able to bind to LDL... (Review)
Review
Apolipoprotein E (apoE) is a plasma lipoprotein which plays a basic role in the degradation of particles rich in cholesterol and triglycerides. It is able to bind to LDL receptors, but also to receptors for chylomicron remnants. There are three major apoE isoforms, E2, E3, and E4. Their role in lipoprotein metabolism is related to their affinity for receptors. Allele E3 is predominant and apoE3 affects metabolism of lipoproteins in a standard way. When compared to allele E3, allele E2 is associated with lower LDL levels, whereas allele E4 with higher LDL levels. This has an impact on the progression of atherosclerosis. Allele E2 exhibits a protective role, whereas allele E4 is associated with a high risk factor. Lipoprotein(a) [Lp(a)] is a plasma lipoprotein, consisting of apolipoprotein(a), linked by a covalent bond with the LDL particle. Increased Lp(a) levels are associated with an increased incidence of diseases based on atherosclerosis, namely the ischemic heart disease. Another effect of Lp(a) is its competition with plasminogen, resulting in a decrease of fibrinolysis and thrombogenic activity. ApoE and Lp(a) are independent risk factors for premature development of atherosclerosis and therefore can be considered as candidate genes of premature atherosclerosis.
Topics: Age of Onset; Alleles; Alzheimer Disease; Animals; Apolipoproteins; Apolipoproteins E; Arteriosclerosis; Genetic Predisposition to Disease; Humans; Hyperlipoproteinemias; Lipoprotein(a); Lipoproteins, LDL; Protein Isoforms
PubMed: 10984073
DOI: No ID Found -
Apolipoprotein Mimetic Peptides: An Emerging Therapy against Diabetic Inflammation and Dyslipidemia.Biomolecules Apr 2021Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous... (Review)
Review
Obesity has achieved epidemic status in the United States, resulting in an increase in type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease. Numerous studies have shown that inflammation plays a key role in the development of insulin resistance and diabetic complications. HDL cholesterol levels are inversely associated with coronary heart disease in humans. The beneficial effect of HDL is due, in part, to apolipoproteins A-I and E, which possess anti-inflammatory properties. The functional quality of HDL, however, may be reduced in the context of diabetes. Thus, raising levels of functional HDL is an important target for reducing inflammation and diabetic complications. Apo A-I possesses eight alpha-helical sequences, most of which form class A amphipathic helical structures. Peptides belonging to this class inhibit atherogenesis in several mouse models. Additional peptides based on structural components of apoE have been shown to mediate a rapid clearance of atherogenic lipoproteins in dyslipidemic mice. In this review, we discuss the efficacy of apolipoprotein mimetic peptides in improving lipoprotein function, reducing inflammation, and reversing insulin resistance and cardiometabolic disease processes in diabetic animals.
Topics: Animals; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins E; Atherosclerosis; Biomimetics; Cardiovascular Diseases; Cholesterol; Diabetes Complications; Diabetes Mellitus, Type 2; Disease Models, Animal; Dyslipidemias; Humans; Inflammation; Mice; Peptides
PubMed: 33922449
DOI: 10.3390/biom11050627