Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia.

Primary hyperchylomicronemia is characterized by marked hypertriglyceridemia exceeding 1,000 mg/dL. It is caused by dysfunctional mutations in specific genes, namely those for lipoprotein lipase (LPL), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), apolipoprotein C2 (ApoC-II), lipase maturation factor 1 (LMF1), or apolipoprotein A5 (ApoA-V). Importantly, antibodies against LPL or GPIHBP1 have also been reported to induce autoimmune hyperchylomicronemia. The patient was a 46-year-old man diagnosed with immune thrombocytopenia (ITP) at 41 years. At the time, he was administered prednisolone (PSL) and eltrombopag, a thrombopoietin receptor agonist. At 44 years, he suffered from acute myocardial infarction, and PSL was discontinued to avoid enhancing atherogenic risks. He was maintained on eltrombopag monotherapy. After discontinuing PSL, marked hypertriglyceridemia (＞3,000 mg/dL) was observed, which did not improve even after a few years of pemafibrate therapy. Upon referral to our clinic, the triglyceride (TG) level was 2,251 mg/dL, ApoC-II was 19.8 mg/dL, LPL was 11.1 ng/mL (0.02-1.5 ng/mL), GPIHBP1 was 47.7 pg/mL (740.0-1,014.0 pg/mL), and anti-GPIHBP1 antibody was detected. The patient was diagnosed to have anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia. He was administered PSL 15 mg/day, and TG levels were controlled at approximately 200 mg/dL. Recent studies have reported that patients with anti-GPIHBP1 antibody-induced autoimmune hyperchylomicronemia had concomitant rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's disease, and Graves' disease. We report a rare case of anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia with concomitant ITP, which became apparent when PSL was discontinued due to the onset of steroid-induced acute myocardial infarction.

MiR-107 Regulates Adipocyte Differentiation and Adipogenesis by Targeting Apolipoprotein C-2 (APOC2) in Bovine.

Adipogenesis is a complex and precisely orchestrated process mediated by a series of adipogenic regulatory factors. Recent studies have highlighted the importance of microRNAs (miRNAs) in diverse biological processes, most specifically in regulating cell differentiation and proliferation. However, the mechanisms of miRNAs in adipogenesis are largely unknown. In this study, we found that miR-107 expression was higher in bovine adipose tissue than that in other tissues, and there was a downregulation trend during adipocyte differentiation. To explore the function of miR-107 in adipocyte differentiation, agomiR-107 and antiagomiR-107 were transfected into bovine adipocytes, respectively. Oil Red O staining, CCK-8, EdU assays, RT-qPCR, and Western blotting were performed, and the results showed that overexpressed miR-107 significantly suppressed fat deposition and adipocyte differentiation, while knockdown of miR-107 promoted fat deposition and adipocytes differentiation. In addition, through bioinformatics analysis, luciferase reporter assays, RT-qPCR, and Western blotting, we identified apolipoprotein 2 (APOC2) as a target of miR-107. Transfection of siRNA-APOC2 into adipocytes led to suppression in adipocyte differentiation and proliferation, suggesting a positive role of APOC2 in bovine lipogenesis. In summary, our findings suggested that miR-107 regulates bovine adipocyte differentiation and lipogenesis by directly targeting APOC2, and these results. These theoretical and experimental basis for future clarification of the regulation mechanism of adipocyte differentiation and lipogenesis. Moreover, for the highly conserved among different species, miR-107 may be a potential molecular target to be used for the treatment of lipid-related diseases in the future.

ScRNA-seq expression of IFI27 and APOC2 identifies four alveolar macrophage superclusters in healthy BALF.

Alveolar macrophages (AMs) reside on the luminal surface of the airways and alveoli, ensuring proper gas exchange by ingesting cellular debris and pathogens, and regulating inflammatory responses. Therefore, understanding the heterogeneity and diverse roles played by AMs, interstitial macrophages, and recruited monocytes is critical for treating airway diseases. We performed single-cell RNA sequencing on 113,213 bronchoalveolar lavage cells from four healthy and three uninflamed cystic fibrosis subjects and identified two MARCKS+LGMN+IMs, FOLR2+SELENOP+ and SPP1+PLA2G7+ IMs, monocyte subtypes, DC1, DC2, migDCs, plasmacytoid DCs, lymphocytes, epithelial cells, and four AM superclusters (families) based on the gene expression of IFI27 and APOC2 These four AM families have at least eight distinct functional members (subclusters) named after their differentially expressed gene(s): IGF1, CCL18, CXCL5, cholesterol, chemokine, metallothionein, interferon, and small-cluster AMs. Interestingly, the chemokine cluster further divides with each subcluster selectively expressing a unique combination of chemokines. One of the most striking observations, besides the heterogeneity, is the conservation of AM family members in relatively equal ratio across all AM superclusters and individuals. Transcriptional data and TotalSeq technology were used to investigate cell surface markers that distinguish resident AMs from recruited monocytes. Last, other AM datasets were projected onto our dataset. Similar AM superclusters and functional subclusters were observed, along with a significant increase in chemokine and IFN AM subclusters in individuals infected with COVID-19. Overall, functional specializations of the AM subclusters suggest that there are highly regulated AM niches with defined programming states, highlighting a clear division of labor.

Apolipoprotein C-II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway.

BACKGROUND: Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism acts as a non-negligible regulator in epithelial-mesenchymal transition (EMT), which is crucial for the metastasis of GC. As apolipoprotein C2 (APOC2) is a key activator of lipoprotein lipase for triglyceride metabolism, the exact mechanism of APOC2 remains largely unknown in GC. METHODS: Tandem mass tags identified differentially expressed proteins between human PM and GC tissues, and showed that APOC2 overexpressed in PM tissues, which was further confirmed by immunoblotting, immunohistochemistry, and ELISA. Global gene expression changes were identified in APOC2 knockdown cells via RNA-sequencing. The role of APOC2 in lipid metabolism of GC cells was assessed via the Seahorse XF analyzer and lipid staining assays. The biological role of APOC2 in GC cells was determined by 3D Spheroid invasion, apoptosis, colony formation, wound healing, transwell assay, and mouse models. The interaction between APOC2 and CD36 was analyzed by co-immunoprecipitation and biolayer interferometry. The underlying mechanisms were investigated using western blot technique. RESULTS: APOC2 overexpressed in GC PM tissues. Upregulation of APOC2 correlated with a poor prognosis in GC patients. APOC2 promoted GC cell invasion, migration, and proliferation via CD36-mediated PI3K/AKT/mTOR signaling activation. Furthermore, APOC2-CD36 axis upregulated EMT markers of GC cells via increasing the phosphorylation of PI3K, AKT, and mTOR. Knockdown either APOC2 or CD36 inhibited the malignant phenotype of cancer cells, and delayed GC PM progression in murine GC models. CONCLUSION: APOC2 cooperates with CD36 to induce EMT to promote GC PM via PI3K/AKT/mTOR pathway. APOC2-CD36 axis may be a potential target for the treatment of aggressive GC.

Apolipoprotein C-II and C-III preferably transfer to both high-density lipoprotein (HDL)2 and the larger HDL3 from very low-density lipoprotein (VLDL).

Triglyceride hydrolysis by lipoprotein lipase (LPL), regulated by apolipoproteins C-II (apoC-II) and C-III (apoC-III), is essential for maintaining normal lipid homeostasis. During triglyceride lipolysis, the apoCs are known to be transferred from very low-density lipoprotein (VLDL) to high-density lipoprotein (HDL), but the detailed mechanisms of this transfer remain unclear. In this study, we investigated the extent of the apoC transfers and their distribution in HDL subfractions, HDL2 and HDL3. Each HDL subfraction was incubated with VLDL or biotin-labeled VLDL, and apolipoproteins and lipids in the re-isolated HDL were quantified using western blotting and high-performance liquid chromatography (HPLC). In consequence, incubation with VLDL showed the increase of net amount of apoC-II and apoC-III in the HDL. HPLC analysis revealed that the biotin-labeled apolipoproteins, including apoCs and apolipoprotein E, were preferably transferred to the larger HDL3. No effect of cholesteryl ester transfer protein inhibitor on the apoC transfers was observed. Quantification of apoCs levels in HDL2 and HDL3 from healthy subjects (n = 8) showed large individual differences between apoC-II and apoC-III levels. These results suggest that both apoC-II and apoC-III transfer disproportionately from VLDL to HDL2 and the larger HDL3, and these transfers might be involved in individual triglyceride metabolism.

Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating hematologic malignancy that affects the hematopoietic stem cells. The 5-year overall survival (OS) of patients with AML is less than 30%, highlighting the urgent need to identify new therapeutic targets. Here, we analyze gene expression datasets for genes that are differentially overexpressed in AML cells compared with healthy hematopoietic cells. We report that apolipoprotein C2 (APOC2) mRNA is significantly overexpressed in AML, particularly in patients with mixed-lineage leukemia rearrangements. By multivariate analysis, high APOC2 expression in leukemia blasts is significantly associated with decreased OS (HR: 2.51; 95% CI, 1.03-6.07; P = 0.04). APOC2 is a small secreted apolipoprotein that constitutes chylomicrons, very-low-density lipoproteins, and high-density lipoproteins with other apolipoproteins. APOC2 activates lipoprotein lipase and contributes to lipid metabolism. By gain and loss of function approaches in cultured AML cells, we demonstrate that APOC2 promotes leukemia growth via CD36-mediated LYN-ERK signaling activation. Knockdown or pharmacological inhibition of either APOC2 or CD36 reduces cell proliferation, induces apoptosis in vitro, and delays leukemia progression in mice. Altogether, this study establishes APOC2-CD36 axis as a potential therapeutic target in AML.

N- and C-terminal regions of αB-crystallin and Hsp27 mediate inhibition of amyloid nucleation, fibril binding, and fibril disaggregation.

Small heat-shock proteins (sHSPs) are ubiquitously expressed molecular chaperones that inhibit amyloid fibril formation; however, their mechanisms of action remain poorly understood. sHSPs comprise a conserved α-crystallin domain flanked by variable N- and C-terminal regions. To investigate the functional contributions of these three regions, we compared the chaperone activities of various constructs of human αB-crystallin (HSPB5) and heat-shock 27-kDa protein (Hsp27, HSPB1) during amyloid formation by α-synuclein and apolipoprotein C-II. Using an array of approaches, including thioflavin T fluorescence assays and sedimentation analysis, we found that the N-terminal region of Hsp27 and the terminal regions of αB-crystallin are important for delaying amyloid fibril nucleation and for disaggregating mature apolipoprotein C-II fibrils. We further show that the terminal regions are required for stable fibril binding by both sHSPs and for mediating lateral fibril-fibril association, which sequesters preformed fibrils into large aggregates and is believed to have a cytoprotective function. We conclude that although the isolated α-crystallin domain retains some chaperone activity against amyloid formation, the flanking domains contribute additional and important chaperone activities, both in delaying amyloid formation and in mediating interactions of sHSPs with amyloid aggregates. Both these chaperone activities have significant implications for the pathogenesis and progression of diseases associated with amyloid deposition, such as Parkinson's and Alzheimer's diseases.

Blood miR-1275 is associated with risk of ischemic stroke and inhibits macrophage foam cell formation by targeting ApoC2 gene.

Apolipoprotein C2 (ApoC2) is an important member of the apolipoprotein C family and functions as a major activator of lipoprotein lipase (LPL). In cardiovascular and cerebrovascular systems, the lipolytic activity of the LPL-ApoC2 complex is critical for the metabolism of triglyceride-rich lipoproteins and contributes to the pathogenesis of ischemic stroke (IS). However, the regulation of ApoC2 in IS development remains unclear. In this study, we first explored potential ApoC2-targeting microRNAs (miRNAs) by bioinformatics tool and compared the miRNA expression profiles in the blood cells of 25 IS patients and 25 control subjects by miRNA microarray. miR-1275 was predicted to bind with the 3' untranslated region of ApoC2, and a significant reduction of blood miR-1275 levels was observed in IS patients. Dual-luciferase reporter assay and quantitative RT-PCR confirmed the regulation of ApoC2 by miR-1275 in THP-1 derived macrophages. miR-1275 also inhibited cellular uptake of ox-LDL and suppressed formation of macrophage foam cell. Furthermore, the whole blood miR-1275 levels were validated in 279 IS patients and 279 control subjects by TaqMan assay. miR-1275 levels were significantly lower in IS cases and logistic regression analysis showed that miR-1275 level was negatively associated with the occurrence of IS (adjusted OR, 0.76; 95% CI, 0.69-0.85; p < 0.001). Addition of miR-1275 to traditional risk factors showed an additive prediction value for IS. Our study shows that blood miR-1275 levels were negatively associated with the occurrence of IS, and miR-1275 might exert an athero-protective role against the development of IS by targeting ApoC2 and blocking the formation of macrophage foam cells.

Apolipoprotein C-II mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach.

Elevated plasma triglyceride (TG) levels are associated with higher risk of atherosclerotic cardiovascular disease. One way to reduce plasma TG is to increase the activity of lipoprotein lipase (LPL), the rate limiting enzyme in plasma TG metabolism. An apolipoprotein (apo) C-II mimetic peptide (18A-CII-a) has been recently developed that stimulated LPL activity in vitro and decreased plasma TG concentration in animal models for hypertriglyceridemia. Since this peptide can serve as a new therapeutic approach for treatment of hypertriglyceridemia, we investigated how 18A-CII-a peptide influences LPL activity in human plasma. We used recently described isothermal titration calorimetry based approach to assess the peptide, which enables the analysis in nearly undiluted human plasma. The 18A-CII-a peptide was 3.5-fold more efficient in stimulating LPL activity than full-length apoC-II in plasma sample from normolipidemic individual. Furthermore, 18A-CII-a also increased LPL activity in hypertriglyceridemic plasma samples. Unlike apoC-II, high concentrations of the 18A-CII-a peptide did not inhibit LPL activity. The increase in LPL activity after addition of 18A-CII-a or apoC-II to plasma was due to the increase of the amount of available substrate for LPL. Measurements with isolated lipoproteins revealed that the relative activation effects of 18A-CII-a and apoC-II on LPL activity were greater in smaller size lipoprotein fractions, such as remnant lipoproteins, low-density lipoproteins and high-density lipoproteins. In summary, this report describes a novel mechanism of action for stimulation of LPL activity by apoC-II mimetic peptides.

Suppression of isoproterenol-induced cardiotoxicity in rats by raspberry ketone via activation of peroxisome proliferator activated receptor-α.

The peroxisome proliferator-activated receptor-α (PPAR-α) controls the lipid and glucose metabolism and also affects inflammation, cell proliferation and apoptosis during cardiovascular disease. Raspberry ketone (RK) is a red raspberry (Rubusidaeus, Family-Rosaceae) plant constituent, which activates PPAR-α. This study was conducted to assess the cardioprotective action of RK against isoproterenol (ISO)-induced cardiotoxicity. Wistar rats were randomly divided into six groups (six rats/group). Rats were orally administered with RK (50, 100 and 200 mg/kg, respectively) and fenofibrate (standard, 80 mg/kg) for 28 days and ISO was administered (85 mg/kg, subcutaneously) on 27th and 28th day. Administration of ISO in rats significantly altered hemodynamic and electrocardiogram patterns, total antioxidant capacity, PPAR-α, and apolipoprotein C-III levels. These myocardial aberrations were further confirmed during infarct size, heart weight to body weight ratio and immunohistochemical assessments (caspase-3 and nuclear factor-κB). RK pretreatment (100 and 200 mg/kg) significantly protected rats against oxidative stress, inflammation, and dyslipidemia caused by ISO as demonstrated by change in hemodynamic, biochemical and histological parameters. The results so obtained were quite comparable with fenofibrate. Moreover, RK was found to have binding affinity with PPAR-α, as confirmed by docking analysis. PPAR-α expression and concentration was also found increased in presence of RK which gave impression that RK probably showed cardioprotection via PPAR-α activation, however direct binding study of RK with PPAR-α is needed to confirm this assumption.

Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils.

Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits in vivo and is an independent risk factor for cardiovascular disease. Lipid-free apoC-II readily self-assembles into twisted-ribbon amyloid fibrils but forms straight, rod-like amyloid fibrils in the presence of low concentrations of micellar phospholipids. Charge mutations exerted significantly different effects on rod-like fibril formation compared to their effects on twisted-ribbon fibril formation. For instance, the double mutant, K30D-D69K apoC-II, readily formed twisted-ribbon fibrils, while the rate of rod-like fibril formation in the presence of micellar phospholipid was negligible. Structural analysis of rod-like apoC-II fibrils, using hydrogen-deuterium exchange and NMR analysis showed exchange protection consistent with a core cross-ß structure comprising the C-terminal 58-76 region. Molecular dynamics simulations of fibril arrangements for this region favoured a parallel cross-ß structure. X-ray fibre diffraction data for aligned rod-like fibrils showed a major meridional spacing at 4.6 Å and equatorial spacings at 9.7, 23.8 and 46.6 Å. The latter two equatorial spacings are not observed for aligned twisted-ribbon fibrils and are predicted for a model involving two cross-ß fibrils in an off-set antiparallel structure with four apoC-II units per rise of the ß-sheet. This model is consistent with the mutational effects on rod-like apoC-II fibril formation. The lipid-dependent polymorphisms exhibited by apoC-II fibrils could determine the properties of apoC-II in renal amyloid deposits and their potential role in the development of cardiovascular disease.

Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism.

Apolipoprotein C-II (apoC-II) is a small exchangeable apolipoprotein found on triglyceride-rich lipoproteins (TRL), such as chylomicrons (CM) and very low-density lipoproteins (VLDL), and on high-density lipoproteins (HDL), particularly during fasting. ApoC-II plays a critical role in TRL metabolism by acting as a cofactor of lipoprotein lipase (LPL), the main enzyme that hydrolyses plasma triglycerides (TG) on TRL. Here, we present an overview of the role of apoC-II in TG metabolism, emphasizing recent novel findings regarding its transcriptional regulation and biochemistry. We also review the 24 genetic mutations in the APOC2 gene reported to date that cause hypertriglyceridemia (HTG). Finally, we describe the clinical presentation of apoC-II deficiency and assess the current therapeutic approaches, as well as potential novel emerging therapies.

APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome.

Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.

Physical and functional interactions between nuclear receptor LXRα and the forkhead box transcription factor FOXA2 regulate the response of the human lipoprotein lipase gene to oxysterols in hepatic cells.

Lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides from triglyceride-rich lipoproteins such as VLDL and chylomicrons in the circulation. Mutations in LPL or its activator apolipoprotein C-II cause hypertriglyceridemia in humans and animal models. The levels of LPL in the liver are low but they can be strongly induced by a high cholesterol diet or by synthetic ligands of Liver X Receptors (LXRs). However, the mechanism by which LXRs activate the human LPL gene is unknown. In the present study we show that LXR agonists increased the mRNA and protein levels as well as the promoter activity of human LPL in HepG2 cells. A promoter deletion analysis defined the proximal -109/-28 region, which contains a functional FOXA2 element, as essential for transactivation by ligand-activated LXRα/RXRα heterodimers. Silencing of endogenous FOXA2 in HepG2 cells by siRNAs or by treatment with insulin compromised the induction of the LPL gene by LXR agonists whereas mutations in the FOXA2 site abolished the synergistic transactivation of the LPL promoter by LXRα/RXRα and FOXA2. Physical and functional interactions between LXRα and FOXA2 were established in vitro and ex vivo. In summary, the present study revealed a novel mechanism of human LPL gene induction by oxysterols in the liver with is based on physical and functional interactions between transcription factors LXRα and FOXA2. This mechanism, which may not be restricted to the LPL gene, is critically important for a better understanding of the regulation of cholesterol and triglyceride metabolism in the liver under healthy or pathological states.

Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition.

Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes. ApoC-III elevates TG in part by inhibiting LPL. ApoC-III likely inhibits LPL by competing for lipid binding. To probe this, we used oil-drop tensiometry to characterize binding of six apoC-III variants to lipid/water interfaces. This technique monitors the dependence of lipid binding on surface pressure, which increases during TG hydrolysis by LPL. ApoC-III adsorption increased surface pressure by upward of 18 mN/m at phospholipid/TG/water interfaces. ApoC-III was retained to high pressures at these interfaces, desorbing at 21-25 mN/m. Point mutants, which substituted alanine for aromatic residues, impaired the lipid binding of apoC-III. Adsorption and retention pressures decreased by 1-6 mN/m in point mutants, with the magnitude determined by the location of alanine substitutions. Trp42 was most critical to mediating lipid binding. These results strongly correlate with our previous results, linking apoC-III point mutants to increased LPL binding and activity at lipid surfaces. We propose that aromatic residues in the C-terminal half of apoC-III mediate binding to TG-rich lipoproteins. Increased apoC-III expression in the hypertriglyceridemic state allows apoC-III to accumulate on lipoproteins and inhibit LPL by preventing binding and/or access to substrate.

Intra- and Intersubunit Ion-Pair Interactions Determine the Ability of Apolipoprotein C-II Mutants To Form Hybrid Amyloid Fibrils.

The apolipoprotein family is structurally defined by amphipathic α-helical regions that interact with lipid surfaces. In the absence of lipid, human apolipoprotein (apo) C-II also forms well-defined amyloid fibrils with cross-ß structure. Formation of this ß-structure is accompanied by the burial of two charged residues, K30 and D69, that form an ion-pair within the amyloid fibril core. Molecular dynamics (MD) simulations indicate these buried residues form both intra- and intersubunit ion-pair interactions that stabilize the fibril. Mutations of the ion-pair (either K30D or D69K) reduce fibril stability and prevent fibril formation by K30D apoC-II under standard conditions. We investigated whether mixing K30D apoC-II with other mutants would overcome this loss of fibril forming ability. Co-incubation of equimolar mixtures of K30D apoC-II with wild-type, D69K, or double-mutant (K30D/D69K) apoC-II promoted the incorporation of K30D apoC-II into hybrid fibrils with increased stability. MD simulations showed an increase in the number of intersubunit ion-pair interactions accompanied the increased stability of the hybrid fibrils. These results demonstrate the important role of both intra- and intersubunit charge interactions in stabilizing apoC-II amyloid fibrils, a process that may be a key factor in determining the general ability of proteins to form amyloid fibrils.

Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines.

The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XVth Symposium of the Society, 3 July-7 July 2016, Uppsala, Sweden, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. An amyloid fibril must exhibit affinity for Congo red and with green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. While congophilia and birefringence remain the gold standard for demonstration of amyloid deposits, new staining and imaging techniques are proving useful. To be included in the nomenclature list, in addition to congophilia and birefringence, the chemical identity of the protein must be unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant changes in the amyloid fibril protein. Each distinct form of amyloidosis is uniquely characterized by the chemical identity of the amyloid fibril protein that deposits in the extracellular spaces of tissues and organs and gives rise to the disease syndrome. The fibril proteins are designated as protein A followed by a suffix that is an abbreviation of the parent or precursor protein name. To date, there are 36 known extracellular fibril proteins in humans, 2 of which are iatrogenic in nature and 9 of which have also been identified in animals. Two newly recognized fibril proteins, AApoCII derived from apolipoprotein CII and AApoCIII derived from apolipoprotein CIII, have been added. AApoCII amyloidosis and AApoCIII amyloidosis are hereditary systemic amyloidoses. Intracellular protein inclusions displaying some of the properties of amyloid, "intracellular amyloid" have been reported. Two proteins which were previously characterized as intracellular inclusions, tau and α-synuclein, are now recognized to form extracellular deposits upon cell death and thus have been included in Table 1 as ATau and AαSyn.

Triglyceride-rich lipoprotein metabolism in women: roles of apoC-II and apoC-III.

BACKGROUND: Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. MATERIAL AND METHODS: The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ). RESULTS: Plasma apoC-II and apoC-III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1 - and VLDL2 -apoB-100 and triglyceride (all P < 0·05). ApoC-II production rate (PR) was positively associated with VLDL1 -apoB-100 concentration, VLDL1 triglyceride concentration and VLDL1 triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1 triglyceride FCR (all P < 0·05). No significant associations were observed between apoC-II and VLDL2 apoB-100 or triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2 -apoB-100 and triglyceride concentrations (all P < 0·05). No significant associations were observed between apoC-III and VLDL-apoB-100 and triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 -apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1 - and VLDL2 -apoB-100 and triglyceride concentrations and FCR. CONCLUSIONS: In women, plasma apoC-II and apoC-III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.