Apolipoprotein C-III Research Articles

Lowering apolipoprotein C-III associates with regression of lipidic plaque materials in type 2 DM patients with coronary artery disease: the pre-specified analysis from the OPTIMAL trial

Abstract Introduction Apolipoprotein CIII (ApoC-III) is a circulating lipoprotein which affects triglyceride-rich lipoprotein metabolism and functionality of high-density lipoproteins. These properties indicate ApoC-III as a potential contributor to atherosclerosis. The OPTIMAL randomized controlled trial (jRCT1052180152) compared the efficacy of continuous glucose monitoring guided versus HbA1c-guided glycemic control on coronary atherosclerosis in Type 2 Diabetes (T2DM) patients by using serial near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS). Given that NIRS/IVUS imaging enables to quantitatively evaluate plaque burden and its lipidic component in vivo, the OPTIMAL study provides an opportunity to elucidate the association of ApoC-III with change in quantity and quality of coronary plaques. Purpose To elucidate whether serial change in ApoC-III affects the degree of atheroma progression and lipidic plaque materials on NIRS/IVUS imaging. Methods The OPTIMAL trial has serially monitored non-culprit lesions in 94 T2DM patients receiving PCI by NIRS/IVUS imaging. Of these, 46 patients (73 lesions) were included into the current analysis. Circulating ApoC-III levels were measured at both baseline and 48 weeks. The relationships of serial change in ApoC-III with NIRS/IVUS-derived measures [total atheroma volume (TAV) and maximum lipid core burden index in a 4-mm segment (maxLCBI4mm)] were analyzed. Results All of study subjects received a statin, and high-intensity statin was used in 65.2% of them. On-treatment LDL-C and HbA1c levels were 1.9±0.5mmol/L and 7.2±0.7%, respectively. On NIRS/IVUS analysis, any regression of TAV and maxLCBI4mm was observed in 71.2 and 38.4% of analyzed lesions, respectively (Table). There was no significant relationship between change in ApoC-III and TAV regression (r=0.02, p=0.89). However, a reduction of ApoC-III was significantly associated with a greater regression of maxLCBI4mm (r=0.26, p=0.03) (Figure). Furthermore, multivariate analysis adjusting for LDL-C and high-intensity statin use demonstrated lowering ApoC-III level as an independent predictor of maxLCBI4mm regression (OR=0.83, 95%CI=0.69-0.99, p=0.04) (Table). Even in patients receiving high-intensity statin, the relationship of change in ApoC-III with regression of maxLCBI4mm still existed (Figure). Conclusion Serial NIRS/IVUS imaging revealed that a reduction of circulating ApoC-III was associated with a greater regression of maxLCBI4mm. Our findings suggest ApoC-III as an important therapeutic target to modulate lipidic plaque materials in T2DM receiving a statin.Tables

SP1 transcriptionally upregulates the expression of APOC3 in KGN cells to promote disease progression by regulating TLR2/NF-κB signalling pathway.

Apolipoprotein C3 (APOC3) is known for its important functions in metabolism-related diseases. However, the function and molecular mechanism of APOC3 in polycystic ovarian syndrome (PCOS) have not been reported. Quantitative polymerase chain reaction and western blot assays were used to detect the expression of APOC3 in KGN cells. Small interference APOC3 (siAPOC3) was applied to reduce APOC3 expression, and the proliferation ability of human granulosa cell line (KGN cells) was measured by cell counting kit-8 and colony formation assays. The protein levels of key genes related to apoptosis were detected by western blot assay. The transcriptional regulator of APOC3 was predicted by the UCSC and PROMO website, and verified by dual luciferase assay. siAPOC3 and pcDNA3.1-specific protein 1 (SP1) vector were co-transfected into KGN cells to detect the function of SP1 and APOC3 in KGN cells. APOC3 was overexpressed in KGN cells, and siAPOC3 transfection significantly reduced the growth ability of KGN cells and increased the apoptosis ability of KGN cells. SP1 directly bound to the promoter of APOC3 and transcriptional regulated APOC3 expression. Overexpression of SP1 increased the growth ability of KGN cells and decreased the apoptosis ability of KGN cells, which were reversed after siAPOC3 transfection. The increased levels of toll-like receptor 2 (TLR2) and p65 phosphorylation (p-P65) nuclear factor kappa B (NF-κB) caused by SP1 overexpression were inhibited by siAPOC3 transfection. APOC3, transcriptionally regulated by SP1, promoted the growth of KGN cells, and inhibited the apoptosis by regulating TLR2/NF-κB signalling pathway.

Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell.

Increased prevalence of cancer in obese individuals is involved with dyslipidemia- induced chronic inflammation and immune suppression. Although apolipoprotein C-III (ApoC3)-transgenic mice (ApoC3TG mice) or poloxamer 407 (P407)-treated mice had hyperlipidemia, CD8+ T cells with upregulated antitumor activities were observed in ApoC3TG mice, and decreased CD8+ T cell activities were observed in P407-treated mice. Increased ApoC3 expression in hepatocellular carcinoma was associated with increased infiltration of CD8+ T cells and predicted survival. Recombinant ApoC3 had no direct effects on CD8+ T cells. The upregulation of CD8+ T cells in ApoC3TG mice was due to cross-talk with context cells, as indicated by metabolic changes and RNA sequencing results. In contrast to dendritic cells, the macrophages of ApoC3TG mice (macrophagesTG) displayed an activated phenotype and increased IL-1β, TNF-α, and IL-6 production. Coculture with macrophagesTG increased CD8+ T cell function, and the adoptive transfer of macrophagesTG suppressed tumor progression in vivo. Furthermore, spleen tyrosine kinase (Syk) activation induced by TLR2/TLR4 cross-linking after ApoC3 ligation promoted cellular phospholipase A2 (cPLA2) activation, which in turn activated NADPH oxidase 2 (NOX2) to promote an alternative mode of inflammasome activation. Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophagesTG. Collectively, the increased antitumor activity of CD8+ T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.

Lipoprotein Lipase/Apolipoprotein Cll Gene Polymorphism in Kurdish Patients With Severe Hypertriglyceridemia.

Background Polymorphisms in thelipoprotein lipase(LPL) and apolipoprotein CII (APO CII)genes have been linked to severe hypertriglyceridemia in several populations. This study investigated the frequency ofLPL-Hind lllandAPO Cll-Ava ll polymorphism among Kurdishpatientswith severe hypertriglyceridemia. Methodology We investigated LPL-Hind llland APO Cll-Ava ll gene polymorphism in a sample of Kurdish patients receiving treatment at Azadi Teaching Hospital in Duhok, Kurdistan Region, Iraq. We included a total of 100 subjects in this study, of which 64 had severe hypertriglyceridemia, and 36 had normotriglyceridemia. There were 56 males and 44 females. We used the polymerase chain reaction-restriction fragment length polymorphism technique to determine the polymorphism of the LPL-Hind lll and APO Cll-Ava ll genes. Results In those with severe hypertriglyceridemia, the most frequent alleles were H+H+LPL-Hind lll polymorphism (42, 65.6%) followed by A1A1APO Cll-Ava ll polymorphism (30, 46.9%), whereas these frequencies were 16 (44.4%) and 6 (16.7%) in those with normotriglyceridemia, respectively. The H+H+ genotype group had considerably higher triglyceride levels and lower high-density lipoprotein cholesterol levels compared with the H-H- genotype group. A similar pattern was observed when comparing the A1A1 and A2A2 genotype groups, with both patterns being statistically significant. Conclusions Our results showed a high frequency of H+H+LPL-Hind III polymorphism in those with hypertriglyceridemia, which may be a hereditary indicator of vulnerability to this condition in the Kurdish population.

FRI092 Rationale And Design Of The Balance Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Of Olezarsen In Patients With Familial Chylomicronemia Syndrome

Abstract Disclosure: V. Alexander: Employee; Self; Ionis Pharmaceuticals Inc. E. Karwatowska-Prokopczuk: Employee; Self; Ionis Pharmaceuticals Inc. E.S. Stroes: Other; Self; Akcea Therapeutics, Ionis Pharmaceuticals Inc., Amgen Inc, Novo Nordisk, AstraZeneca, Esperion. C. Ballantyne: Speaker; Self; Ionis Pharmaceuticals Inc. H.N. Ginsberg: None. S. Xia: Employee; Self; Ionis Pharmaceuticals Inc. J. Witztum: Consulting Fee; Self; Ionis Pharmaceuticals Inc. S. Tsimikas: Employee; Self; Ionis Pharmaceuticals Inc. Background: Familial chylomicronemia syndrome (FCS) is a rare genetic cause of severe hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). Currently, there are no approved therapies for the treatment of FCS in the United States, and the absence of lipoprotein lipase (LPL) activity in FCS limits the effectiveness of current treatment options. Olezarsen, a ligand-conjugated antisense oligonucleotide (ASO), inhibits hepatic production of apolipoprotein (apo) C-III, a key regulator of LPL-mediated triglyceride (TG) lipolysis and non-LPL-mediated TG-rich lipoprotein hepatic uptake. In a phase 2 study of non-FCS patients with fasting serum TG levels of 200–500 mg/dL, olezarsen demonstrated reduction in fasting TG levels of up to 60% vs placebo (PBO). The Balance trial (NCT04568434) will evaluate the efficacy and safety of olezarsen as well as the rates of AP in patients with FCS. Methods: Balance is a phase 3, randomized, double-blind, PBO-controlled trial. Key inclusion criteria are genetic confirmation of FCS, fasting TG ≥ 880 mg/dL, and possible history of pancreatitis. Key exclusion criteria include clinically significant abnormalities in medical history such as major surgery within 3 mos of screening and active pancreatitis within 4 wks of screening. Patients will maintain ≤ 20 g daily fat intake and most will receive lipid-lowering medications per local standard of care. Results: Eligible patients (N=66) were enrolled at 29 sites (across 11 countries) and randomized 2:1 to receive one of two doses of olezarsen or PBO over a 53-wk treatment period, followed by post-treatment evaluation or entry into an open-label extension study. Enrollment was monitored to ensure that ≥ 65% of patients had history of pancreatitis within 10 yrs. Reported baseline parameters are preliminary. Of enrolled patients, mean age is 45±13.4 yrs, 58% of the population are female, and mean body mass index is 24.0 kg/m2; 83% had a history of hospitalization for AP, or severe abdominal pain episode, or symptoms suggestive of pancreatitis, with a mean of 2.4 episodes over the last 5 yrs and 5.1 over the last 10 yrs. Median fasting TG level is 2334.5 mg/dL. The primary efficacy endpoint of the study is percent change in fasting TG from baseline (BL) at 6 mos with olezarsen compared to PBO. Secondary endpoints (olezarsen vs PBO) include percent change in fasting TG from BL at 12 mos, achievement of ≥ 40% or ≥ 70% fasting TG reduction at 6 mos, patient proportions ≤ 500 mg/dL or ≤ 750 mg/dL at 6 mos, and adjudicated AP event rates. Exploratory assessments include patient-reported symptoms such as abdominal pain and health-related quality of life. Safety and tolerability assessments include adverse events and laboratory tests. Conclusion: Balance is designed to determine whether the apoC-III ASO olezarsen, added to standard of care, safely reduces TG levels and the rate of AP in patients with FCS. Presentation: Friday, June 16, 2023

Inhibition of Apoc1 reverses resistance of sorafenib by promoting ferroptosis in esophageal cancers

Drug resistance is an obstacle in therapy of esophageal cancers (ECs), and the role of ferroptosis in progression ECs is still not clearly clarified. In the present study, we investigated the role of Apolipoprotein C1 (Apoc1) in regulating the sorafenib resistance in EC cells. Apoc1 was knock down after infection with Apoc1 shRNA lentivirus and stable cell lines for Apoc1 knockdown were screened. Cell viabilities were tested by MTT assay. ROS, MDA, and GSH tested by specific kits. In vivo experiment in nude mice were performed to test the correlation of Apoc1 and ferroptosis. The expression of Apoc1 and GPX4 was tested by western blotting. The results showed that Apoc1 was highly expressed in EC tissues and associated with poor overall survival rate of EC. Knockdown Apoc1 overcame resistance of sorafenib in EC cells and promoted erastin and sorafenib induced ferroptosis by upregulating the levels of ROS and MDA and downregulating the level of GSH in OE19/Sora and EC109/Sora cells. Rescue experiments proved that Apoc1 regulated sorafenib induced ferroptosis via GPX4. Furthermore, knockdown of Apoc1 inhibited the tumor progression by promoting ferroptosis in nude mice. In conclusion, knockdown Apoc1 overcome resistance of sorafenib in EC cells and in vivo by promoting sorafenib induced ferroptosis via GPX4. Targeting Apoc1 might be an effective way to reverse the drug resistance of sorafenib via inducing ferroptosis in EC progression.

Updates in Small Interfering RNA for the Treatment of Dyslipidemias.

Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Serum APOC1 levels are decreased in young autoantibody positive children who rapidly progress to type 1 diabetes

Better understanding of the early events in the development of type 1 diabetes is needed to improve prediction and monitoring of the disease progression during the substantially heterogeneous presymptomatic period of the beta cell damaging process. To address this concern, we used mass spectrometry-based proteomics to analyse longitudinal pre-onset plasma sample series from children positive for multiple islet autoantibodies who had rapidly progressed to type 1 diabetes before 4 years of age (n = 10) and compared these with similar measurements from matched children who were either positive for a single autoantibody (n = 10) or autoantibody negative (n = 10). Following statistical analysis of the longitudinal data, targeted serum proteomics was used to verify 11 proteins putatively associated with the disease development in a similar yet independent and larger cohort of children who progressed to the disease within 5 years of age (n = 31) and matched autoantibody negative children (n = 31). These data reiterated extensive age-related trends for protein levels in young children. Further, these analyses demonstrated that the serum levels of two peptides unique for apolipoprotein C1 (APOC1) were decreased after the appearance of the first islet autoantibody and remained relatively less abundant in children who progressed to type 1 diabetes, in comparison to autoantibody negative children.

ApoC3 is expressed in oocytes and increased expression is associated with PCOS progression

BackgroundPolycystic ovary syndrome (PCOS) is a lifelong metabolic disorder and the most common cause of anovulatory infertility affecting women in reproductive age. Our recent study reported that apolipoprotein C3 (ApoC3) could be a potential diagnostic serum marker for metabolism disturbance in PCOS patients, but whether it is present in the ovaries and what role it plays has not yet been described.ObjectiveAimed to investigate ApoC3 expression in ovary of PCOS, and to discuss its potential role in PCOS progression.MethodsApoC3 expression in ovarian tissue samples from 12 PCOS patients along with 12 healthy controls were measured via immunohistochemistry (IHC). Also, the level of ApoC3 in follicular fluid from 14 patients diagnosed with PCOS and 13 control subjects were detected by ELISA. The expression and location of ApoC3 in ovaries of PCOS mice were tested weekly for three consecutive weeks during PCOS formation using real time PCR, Western Blot, IHC and immunofluorescence. The relation of ApoC3 and sex hormones was analyzed in mouse plasma. Additionally, the dynamic changes of ApoC3 level in ovaries of healthy mice during postnatal development was also investigated.ResultsApoC3 levels in ovarian tissue and follicular fluid were significantly higher in PCOS patients than in controls (33.87 ± 4.11 vs. 27.71 ± 3.65, P < 0.01; 0.87 ± 0.09 vs. 0.51 ± 0.32 ng/mL, P < 0.05), respectively. In ovary, ApoC3 was found to be located in the cytoplasm of oocyte, and its expression gradually increased with PCOS progression (P < 0.05). Furthermore, correlation analysis showed that plasma ApoC3 level was closely associated with luteinizing hormone (r = 0.709, P = 0.001), testosterone (r = 0.627, P = 0.005) and anti-mullerian hormone (r = 0.680, P = 0.002) in PCOS mice. In addition, ApoC3 level in oocyte was physiologically increased and peaked on postnatal age 21 (P21), then decreased following P21 in healthy mice.ConclusionsWe identified ApoC3 expression in oocyte. It may be involved in PCOS progression and possibly participate in the regulation of oocyte development.

Unanticipated Enhancement of Intestinal TG Output by Apoc3 ASO Inhibition.

The objective of this study was to investigate whether apoC3 (apolipoprotein C3) inhibition with an antisense oligonucleotide (ASO) modulates intestinal triglyceride secretion. Sprague-Dawley rats were treated with subcutaneous injections of apoC3 ASO 25 mg/kg twice weekly or inactive ASO for 4 weeks before the assessment of lymph flow, triglyceride and apoB48 appearance in the lymph. Rats were surgically implanted with catheters in the mesenteric lymph duct and duodenum. Following an overnight fast, an intraduodenal lipid bolus (1.5-mL intralipid) was administered. Lymph fluid was collected for the following 4 hours to compare effects on lymph flow, lymph triglyceride and apoB48 concentration, and secretion. To assess suppression of apoC3 expression and protein abundance by apoC3 ASO compared with inactive ASO (placebo), intestinal and hepatic tissues were collected from a subset of animals before (fasting) and after an enteral lipid bolus (post-lipid). ApoC3 ASO significantly reduced apoC3 mRNA expression in the liver compared with inactive ASO (fasting: 42%, P=0.0048; post-lipid: 66%, P<0.001) and in the duodenum (fasting: 29%, P=0.0424; post-lipid: 53%, P=0.0120). As expected, plasma triglyceride also decreased significantly (fasting: 74%, P<0.001; post-lipid: 33%, P=0.0276). Lymph flow and cumulative lymph volume remained unchanged following apoC3 ASO therapy; however, lymph triglyceride, but not apoB48 output, increased by 38% (ANOVA, P<0.001). Last, no changes were observed in stool triglyceride, intestinal fat (quantified via oil red O staining), and expression of mRNAs involved in triglyceride synthesis, lipid droplet formation, and chylomicron transport and secretion. Despite the marked reduction in plasma triglyceride concentration that occurs with apoC3 ASO inhibition, intestinal triglyceride output surprisingly increased rather than decreased. These data demonstrate that the reduction of intestinal triglyceride output does not contribute to the potent plasma triglyceride-lowering observed with this novel therapy for hypertriglyceridemia. Further studies are required to explore the mechanism of this intestinal effect.

Association Between Apolipoprotein C-3 SstⅠ Polymorphism and Serum Lipids in Patients With Gestational Diabetes Mellitus

To investigate the apolipoprotein C-3 (APOC3) gene Sst Ⅰ polymorphism and its relationship with changes in serum lipids in patients with gestational diabetes mellitus (GDM). A total of 630 pregnant women with GDM and 1027 normal pregnant controls were covered in the study. The genotype and allele frequencies of APOC3 Sst Ⅰ polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence. Apolipoproteins A 1 (apoA1) and B (apoB) levels were measured by turbidimetric immunoassay. The allele frequencies of S1 and S2 of the APOC3 polymorphism at the SstⅠ locus were 0.704 and 0.296 in the GDM group and 0.721 and 0.279 in the control group, respectively. There was no significant difference in genotype frequency and allele frequency of APOC3 Sst Ⅰ polymorphism between the GDM and the control groups ( P>0.05). In the GDM group, those with S2S2 and S1S2 genotypes had higher plasma HDL-C levels and lower atherogenic index (AI) values than those with S1S1 genotype did, with the differences being statistically significant (all P<0.05). GDM patients were then divided into obesity and non-obesity subgroups. Further subgroup analysis showed that the association of APOC3 genotype with changes in HDL-C levels was observed only in obese GDM patients, while the association of APOC3 genotype with changes in AI values was observed in both obese and nonobese patients. In addition, in obese GDM patients, those with S2S2 genotype had significantly higher plasma TG levels than those with S1S1 and S1S2 genotypes did ( P<0.05 and P<0.01, respectively). In non-obese GDM patients, those with S2S2 genotype had significantly lower apoB/apoA1 ratio than S2S2 carriers did ( P<0.05). No genotype-related effect on lipid and apolipoprotein variations was evident in the normal controls. APOC3 Sst Ⅰ polymorphism in GDM patients is associated with HDL-C and TG levels as well as AI value and apoB/apoA1 ratio. The changes in lipid levels and apolipoprotein ratio showed BMI-dependent features. However, association between polymorphism at the locus and the development of GDM was not observed.

Nanoparticle (NP)-mediated APOC1 silencing to inhibit MAPK/ERK and NF-κB pathway and suppress breast cancer growth and metastasis.

Breast cancer is one of the most common malignant tumors with high mortality and poor prognosis in women. There is an urgent need to discover new therapeutic targets for breast cancer metastasis. Herein, we identified that Apolipoprotein C1 (APOC1) was up-regulated in primary tumor of breast cancer patient that recurrence and metastasis by immunohistochemistry (IHC). Kaplan-Meier Plotter database showed that high levels of APOC1 in breast cancer patients were strongly associated with worse overall survival (OS) and relapse-free survival (RFS). Mechanistically, APOC1 silencing significantly inhibits MAPK/ERK kinase pathway and restrains the NF-κB to decrease the transcription of target genes related to growth and metastasis in vitro. Based on this regulatory mechanism, we developed these findings into potential therapeutic drugs, glutathione (GSH) responsive nano-particles (NPs) were used for systemic APOC1 siRNA delivery, NPs (siAPOC1) silenced APOC1 expression, and subsequently resulted in positive anti-tumor effects in orthotopic and liver metastasis models in vivo. Taken together, GSH responsive NP-mediated siAPOC1 delivery was proved to be effective in regulating growth and metastasis in multiple tumor models. These findings show that APOC1 could be a potential biomarker to predict the prognosis of breast cancer patients and NP-mediated APOC1 silencing could be new strategies for exploration of new treatments for breast cancer metastasis.

Sugar and Dyslipidemia: A Double-Hit, Perfect Storm.

The availability of sugar has expanded over the past 50 years, due to improved industrial processes and corn subsidies, particularly in the form of sweetened beverages. This correlates with a surge in the prevalence of cardiometabolic disorders, which has brought this issue back into the spotlight for public health. In this narrative review, we focus on the role of fructose in the genesis of cardiometabolic dyslipidemia (an increase in serum triglyceride-rich lipoproteins (TRL): VLDL, chylomicrons (CM), and their remnants) bringing together the most recent data on humans, which demonstrates the crucial interaction between glucose and fructose, increasing the synthesis while decreasing the catabolism of these particles in a synergistic downward spiral. After reviewing TRL metabolism, we discuss the fundamental principles governing the metabolism of fructose in the intestine and liver and the effects of dysregulated fructolysis, in conjunction with the activation of carbohydrate-responsive element-binding protein (ChREBP) by glucose and the resulting crosstalk. The first byproduct of fructose catabolism, fructose-1-P, is highlighted for its function as a signaling molecule that promotes fat synthesis. We emphasize the role of fructose/glucose interaction in the liver, which enhances de novo lipogenesis, triglyceride (TG) synthesis, and VLDL production. In addition, we draw attention to current research that demonstrates how fructose affects the activity of lipoprotein lipase by increasing the concentration of inhibitors such as apolipoprotein CIII (apoCIII) and angiopoietin-like protein 3 (ANGPTL3), which reduce the catabolism of VLDL and chylomicrons and cause the building up of their atherogenic remnants. The end outcome is a dual, synergistic, and harmful action that encourages atherogenesis. Thus, considering the growing concerns regarding the connection between sugar consumption and cardiometabolic disease, current research strongly supports the actions of public health organizations aimed at reducing sugar intake, including dietary guidance addressing "safe" limits for sugar consumption.

Advances in Treatment of Dyslipidemia.

Dyslipidemias have emerged as prevalent disorders among patients, posing significant risks for the development and progression of cardiovascular diseases. These conditions are characterized by elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C). This review delves into the current treatment approach, focusing on equalizing these parameters while enhancing the overall quality of life for patients. Through an extensive analysis of clinical trials, we identify disorders that necessitate alternative treatment strategies, notably familial hypercholesterolemia. The primary objective of this review is to consolidate existing information concerning drugs with the potential to revolutionize dyslipidemia management significantly. Among these promising pharmaceuticals, we highlight alirocumab, bempedoic acid, antisense oligonucleotides, angiopoietin-like protein inhibitors, apolipoprotein C-III (APOC3) inhibitors, lomitapide, and cholesterol ester transfer protein (CETP) inhibitors. Our review demonstrates the pivotal roles played by each of these drugs in targeting specific parameters of lipid metabolism. We outline the future landscape of dyslipidemia treatment, envisaging a more tailored and effective therapeutic approach to address this widespread medical concern.

Targeted serum proteomics of longitudinal samples from newly diagnosed youth with type 1 diabetes distinguishes markers of disease and C-peptide trajectory

Aims/hypothesisThere is a growing need for markers that could help indicate the decline in beta cell function and recognise the need and efficacy of intervention in type 1 diabetes. Measurements of suitably selected serum markers could potentially provide a non-invasive and easily applicable solution to this challenge. Accordingly, we evaluated a broad panel of proteins previously associated with type 1 diabetes in serum from newly diagnosed individuals during the first year from diagnosis. To uncover associations with beta cell function, comparisons were made between these targeted proteomics measurements and changes in fasting C-peptide levels. To further distinguish proteins linked with the disease status, comparisons were made with measurements of the protein targets in age- and sex-matched autoantibody-negative unaffected family members (UFMs).MethodsSelected reaction monitoring (SRM) mass spectrometry analyses of serum, targeting 85 type 1 diabetes-associated proteins, were made. Sera from individuals diagnosed under 18 years (n=86) were drawn within 6 weeks of diagnosis and at 3, 6 and 12 months afterwards (288 samples in total). The SRM data were compared with fasting C-peptide/glucose data, which was interpreted as a measure of beta cell function. The protein data were further compared with cross-sectional SRM measurements from UFMs (n=194).ResultsEleven proteins had statistically significant associations with fasting C-peptide/glucose. Of these, apolipoprotein L1 and glutathione peroxidase 3 (GPX3) displayed the strongest positive and inverse associations, respectively. Changes in GPX3 levels during the first year after diagnosis indicated future fasting C-peptide/glucose levels. In addition, differences in the levels of 13 proteins were observed between the individuals with type 1 diabetes and the matched UFMs. These included GPX3, transthyretin, prothrombin, apolipoprotein C1 and members of the IGF family.Conclusions/interpretationThe association of several targeted proteins with fasting C-peptide/glucose levels in the first year after diagnosis suggests their connection with the underlying changes accompanying alterations in beta cell function in type 1 diabetes. Moreover, the direction of change in GPX3 during the first year was indicative of subsequent fasting C-peptide/glucose levels, and supports further investigation of this and other serum protein measurements in future studies of beta cell function in type 1 diabetes.Graphical

Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention.

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.

Protein Corona of Anionic Fluid-Phase Liposomes Compromises Their Integrity Rather than Uptake by Cells.

Despite the undisputable role of the protein corona in the biointeractions of liposome drug carriers, the field suffers from a lack of knowledge regarding the patterns of protein deposition on lipid surfaces with different compositions. Here, we investigated the protein coronas formed on liposomes of basic compositions containing combinations of egg phosphatidylcholine (PC), palmitoyloleoyl phosphatidylglycerol (POPG), and cholesterol. Liposome-protein complexes isolated by size-exclusion chromatography were delipidated and analyzed using label-free LC-MS/MS. The addition of the anionic lipid and cholesterol both affected the relative protein abundances (and not the total bound proteins) in the coronas. Highly anionic liposomes, namely those containing 40% POPG, carried corona enriched with cationic proteins (apolipoprotein C1, beta-2-glycoprotein 1, and cathelicidins) and were the least stable in the calcein release assay. Cholesterol improved the liposome stability in the plasma. However, the differences in the corona compositions had little effect on the liposome uptake by endothelial (EA.hy926) and phagocytic cells in the culture (U937) or ex vivo (blood-derived monocytes and neutrophils). The findings emphasize that the effect of protein corona on the performance of the liposomes as drug carriers occurs through compromising particle stability rather than interfering with cellular uptake.

Lipids and apolipoproteins C-III and E among treatment-naïve and treatment-experienced persons with HIV in Nigeria.

Dyslipidaemia is a known cause of cardiovascular mortality. Persons living with HIV are at high risk of developing cardiovascular disease due to lipid metabolism disorders associated with HIV or its therapy. This study evaluated concentrations of lipoproteins and apolipoprotein C-III and E, as a way of assessing cardiometabolic risks among HIV patients. We enrolled 50 HIV-negative persons and 100 HIV-positive patients, 50 on antiretroviral therapy (ART) and 50 treatment-naïve persons, from the Central Hospital and the Stella Obasanjo Hospital, Benin City, Edo State, Nigeria, between May 2015 and November 2015. Participants with a history of metabolic abnormalities were excluded. Apolipoproteins were assessed by enzyme-linked immunosorbent assay, while lipids were measured by spectrophotometry. There were significant abnormalities in the lipid profile of patients with HIV. Triglycerides levels of HIV patients (ART-naïve: 1.44 ± 0.65 mmol/L; p < 0.001 and ART-experienced: 1.49 ± 0.70 mmol/L; p = 0.001) were significantly higher than among controls (0.95 ± 0.54 mmol/L). HIV patients had higher concentrations of apolipoprotein C-III than controls (p < 0.001) and higher low-density lipoprotein cholesterol levels (treatment-naïve: 2.83 mmol/L and ART-experienced patients: 3.59 mmol/L) than controls (2.50 mmol/L; p = 0.003). Conversely, HIV patients had significantly lowered high-density lipoprotein cholesterol levels compared to controls (p < 0.001). Dyslipidaemia was observed among HIV participants, irrespective of their ART experience. Therefore, it is crucial that the lipids of HIV patients be closely monitored to enable early intervention and decrease cardiovascular death. This study affirms that dyslipidemia is a complication of HIV or the prolonged use of ART.

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as “remnants”, is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.

Protective Association of APOC1/rs4420638 with Risk of Obesity: A case-control Study in Portuguese Children

The association of the rs4420638 polymorphism, near the APOC1 gene, was examined with the risk of obesity among Portuguese children. A sample of 446 Portuguese individuals (231 boys and 215 girls) of European descent, aged 3.2 to 13.7 years old (mean age: 7.98 years), were selected to conduct a case-control study. Body mass index (BMI), BMI Z-scores, and waist circumference were calculated. Genotyping was performed by real time PCR using a pre-designed TaqMan probe. Logistic regression and the nonparametric Mann-Whitney test were used to test the associations. The association results revealed a significant protective effect from the minor G-allele of SNP rs4420638 against obesity, with an odds ratio (OR) of 0.619 (95% CI 0.421–0.913; p = 0.0155) in the additive model, and OR of 0.587 (95% CI 0.383-0.9; p = 0.0145) in the dominant model. Moreover, comparing genotype groups (AA vs. AG + GG), significantly lower values (p < 0.05) for the anthropometric traits weight, height, BMI, BMI Z-score and waist circumference, were observed in the carriers of allele G. The present study provides further evidence for the APOE/APOC1 candidate-region association with the risk of obesity. This was the first study to describe the protective association of the rs4420638 minor G-allele against obesity in childhood exclusively.