Apolipoprotein C3 (ApoC3) facilitates NLRP3 mediated pyroptosis of macrophages through mitochondrial damage by accelerating of the interaction between SCIMP and SYK pathway in acute lung injury.

Respiratory failure caused by severe acute lung injury (ALI) is the main cause of mortality in patients with COVID-19.This study aimed to investigate the effects and underlying biological mechanism of Apolipoprotein C3 (ApoC3) in ALI. To establish an in vivo model, C57BL/6 mice were exposed by lipopolysaccharide (LPS). For the in vitro model, murine bone marrow-derived macrophages (BMDMs) or RAW264.7 cells were stimulated with LPS + adenosine triphosphate (ATP). Serum levels of ApoC3 were found to be upregulated in patients with COVID-19 or pneumonia-induced ALI. Inhibition of ApoC3 reduced lung injury in an ALI model, while overexpression of ApoC3 promoted lung injury. ApoC3 induced mitochondrial damage-mediated pyroptosis in ALI through the activation of the NOD-like receptorprotein 3 (NLRP3) inflammasome. ApoC3 recombinant protein significantly increased SCIMP expression in the lung tissue of mice models with ALI. ApoC3 also facilitated the interaction between the SLP adapter and CSK-interacting membrane protein (SCIMP) protein and Spleen tyrosine kinase (SYK) protein in the ALI model. Moreover, ApoC3 accelerated calcium-dependent reactive oxygen species (ROS) production in the ALI model. The effects of ApoC3 on pyroptosis were mitigated by the use of a pyroptosis inhibitor or an ROS inhibitor in the ALI model. Furthermore, ApoC3 activated the expression of SYK, which in turn induced NLRP3 inflammasome-regulated pyroptosis in the ALI model. METTL3 was found to mediate the m6A mRNA expression of ApoC3. Overall, our study highlights the crucial role of ApoC3 in promoting macrophage pyroptosis in ALI through calcium-dependent ROS production and NLRP3 inflammasome activation via the SCIMP-SYK pathway, providing a potential therapeutic strategy for ALI and other inflammatory diseases.

[Association Between Apolipoprotein C-3 Sstâ Polymorphism and Serum Lipids in Patients With Gestational Diabetes Mellitus].

Objective: 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). Methods: 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. Results: 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. Conclusion: 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.

Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids.

Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII0a), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII0c, apo-CIII1 and apo-CIII2). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes (n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System (n = 5409). Rs4846913-A, in the GALNT2-gene, was associated with decreased apo-CIII0a. This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172-gene, was associated with decreased apo-CIII2 and with hypertriglyceridemia. In line, apo-CIII2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2-gene plays a major role i O-glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172/NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O-glycosylation in health and disease.

Association of apolipoproteins C-I and C-II truncations with coronary heart disease and progression of coronary artery calcium: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Higher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I'/C-I) and C-II (C-II'/C-II) are associated with less atherogenic lipid profiles. We examined prospective relationships of C-I'/C-II and C-II'/C-II with coronary heart disease (CHD) and coronary artery calcium (CAC). METHODS: ApoC-I and apoC-II proteoforms were measured by mass spectrometry immunoassay in 5790 MESA baseline plasma samples. CHD events (myocardial infarction, resuscitated cardiac arrest, fatal CHD, n = 434) were evaluated for up to 17 years. CAC was measured 1-4 times over 10 years for incident CAC (if baseline CAC = 0), and changes (follow-up adjusted for baseline) in CAC score and density (if baseline CAC>0). RESULTS: C-II'/C-II was inversely associated with CHD (n = 434 events) after adjusting for non-lipid cardiovascular risk factors (Hazard ratio: 0.89 [95% CI: 0.81-0.98] per SD), however, the association was attenuated after further adjustment for HDL levels (0.93 [0.83-1.03]). There was no association between C-I'/C-I and CHD (0.98 [0.88-1.08]). C-II'/C-II was positively associated with changes in CAC score (3.4% [95%CI: 0.6, 6.3]) and density (6.3% [0.3, 4.2]), while C-I'/C-I was inversely associated with incident CAC (Risk ratio: 0.89 [95% CI: 0.81, 0.98]) in fully adjusted models that included plasma lipids. Total apoC-I and apoC-II concentrations were not associated with CHD, incident CAC or change in CAC score. CONCLUSIONS: Increased apoC-II truncation was associated with reduced CHD, possibly explained by differences in lipid metabolism. Increased apoC-I and apoC-II truncations were also associated with less CAC progression and/or development of denser coronary plaques.

Antioxidant defense enzymes in multiple sclerosis: A 5-year follow-up study.

BACKGROUND AND PURPOSE: Oxidative stress biomarkers are increased in multiple sclerosis (MS) lesions. Antioxidant defense enzymes regulate reactive oxygen species that can cause tissue injury in MS. METHODS: The study of 91 subjects included 64 relapsing-remitting MS (RR-MS; 72% female, baseline age ± SD = 44.6 ± 11 years, disease duration = 13.3 ± 8.8 years, median Expanded Disability Status Scale [EDSS] = 2.0, interquartile range = 1.8) and 27 healthy controls (HC) at baseline and 5-year follow-up (5YFU). Serum glutathione peroxidase (GPX), glutathione-S-transferase (GST), glutathione reductase (GSHR), superoxide dismutase, and paraoxonase-1 (PON1) arylesterase and paraoxonase activities were measured using kinetic enzyme assays. Total cholesterol (TC), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and an apolipoprotein (Apo) panel with ApoA-I, ApoA-II, ApoB, ApoC-II, and ApoE were obtained. Serum neurofilament (sNfL) was used to assess axonal injury. Disability was measured on the EDSS. RESULTS: GSHR activity was lower in HC compared to RR-MS at baseline and 5YFU. GPX (p = 0.008) and PON1 arylesterase and paraoxonase activities (both p = 0.05) increased between baseline and 5YFU in HC but did not increase in RR-MS. At baseline and 5YFU, GPX and GST were associated with TC, LDL-C, and ApoA-II; GSHR was associated with ApoA-II and ApoC-II. Antioxidant enzymes were not associated with sNfL or EDSS in RR-MS. CONCLUSIONS: RR-MS patients did not exhibit the changes in antioxidant enzyme activities over 5YFU found in HC; however, the differences were modest. Antioxidant enzyme activities are not associated with disability.

Cholesterol pathway biomarkers are associated with neuropsychological measures in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) is frequent in persons with multiple sclerosis (PwMS) and is linked to neurodegeneration. Cholesterol pathway biomarkers (CPB) are associated with blood-brain barrier breakdown, lesions, and neurodegeneration in multiple sclerosis (MS). CPB could influence CI. METHODS: This cross-sectional study (n = 163) included 74 relapsing-remitting MS (RR-MS), 48 progressive MS (P-MS) and 41 healthy control (HC) subjects. The assessed physical disability and cognitive measures were: Nine-hole Peg Test (NHPT), Timed 25-Foot Walk, Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test-3, and Beck Depression Inventory-Fast Screen. CPB panel included plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and the apolipoproteins (Apo), ApoA-I, ApoA-II, ApoB, ApoC-II and ApoE. Disability and cognitive measures were assessed as dependent variables in regression analyzes with age, sex, body mass index, years of education, HC vs. RR-MS vs. P-MS status, CPB, and a HC vs. RR-MS vs. P-MS status × CPB interaction term as predictors. RESULTS: SDMT was associated with the interaction terms for HDL-C (p = 0.045), ApoA-I (p = 0.032), ApoB (p = 0.032), TC/HDL-C (p = 0.013), and ApoB/ApoA-I (p = 0.008) ratios. CPB associations of SDMT were not abrogated upon adjusting for brain parenchymal volume. NHPT performance was associated with the interaction terms for TC (p = 0.047), LDL-C (p = 0.017), ApoB (p = 0.001), HDL-C (p = 0.035), ApoA-I (p = 0.032), ApoC-II (p = 0.049) and ApoE (p = 0.037), TC/HDL-C (p < 0.001), and ApoB/ApoA-I ratios (p < 0.001). CONCLUSIONS: The LDL to HDL proportion is associated with SDMT and NHPT in MS. The findings are consistent with a potential role for CPB in CI.

Surface charge influences protein corona, cell uptake and biological effects of carbon dots.

Carbon dots are emerging nanoparticles (NPs) with tremendous applications, especially in the biomedical field. Herein is reported the first quantitative proteomic analysis of the protein corona formed on CDs with different surface charge properties. Four CDs were synthesized from citric acid and various amine group-containing passivation reagents, resulting in cationic NPs with increasing zeta (ζ)-potential and density of positive charges. After CD contact with serum, we show that protein corona identity is influenced by CD surface charge properties, which in turn impacts CD uptake and viability loss in macrophages. In particular, CDs with high ζ-potential (>+30 mV) and charge density (>2 µmol mg-1) are the most highly internalized, and their cell uptake is strongly correlated with a corona enriched in vitronectin, fibulin, fetuin, adiponectin and alpha-glycoprotein. On the contrary, CDs with a lower ζ-potential (+11 mV) and charge density (0.01 µmol mg-1) are poorly internalized, while having a corona with a very different protein signature characterized by a high abundance of apolipoproteins (APOA1, APOB and APOC), albumin and hemoglobin. These data illustrate how corona characterization may contribute to a better understanding of CD cellular fate and biological effects, and provide useful information for the development of CDs for biomedical applications.

Differences in HDL-Bound Apolipoproteins in Patients With Advanced Liver Fibrosis Due to Nonalcoholic Fatty Liver Disease.

CONTEXT: The mechanisms leading to increased cardiovascular disease in patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis remain incompletely understood. OBJECTIVE: This study assessed HDL-bound proteins in patients with NAFLD with or without advanced fibrosis. METHODS: This cross-sectional study at a university hospital included 185 patients with or without type 2 diabetes (T2D). Patients underwent liver proton magnetic resonance spectroscopy to measure intrahepatic triglyceride accumulation and those with NAFLD underwent a percutaneous liver biopsy. Advanced lipid testing with lipoprotein subfraction measurements and targeted proteomics of HDL-bound proteins was performed. RESULTS: Patients with and without advanced fibrosis had similar clinical characteristics, except for lower HDL-C (34 ± 8 vs 38 ± 9 mg/dL, P = 0.024) and higher prevalence of T2D in advanced fibrosis. Patients with advanced fibrosis had lower HDL particle number. A panel of 28 HDL-bound proteins were targeted and quantified by multiple reaction monitoring liquid chromatography-tandem mass spectrometry. Five proteins were found to be decreased in patients with advanced fibrosis (ApoC-I [P < 0.001], ApoC-IV [P = 0.012], ApoM [P = 0.008], LCAT [P = 0.014], and SAA4 [P = 0.016]). No differences were observed in these proteins in patients with vs without NAFLD or steatohepatitis. The pCAD index, associated with coronary artery disease and cardiovascular mortality, was significantly higher in patients with advanced fibrosis (97 ± 5 vs 86 ± 25, P = 0.04). CONCLUSION: Patients with NAFLD with advanced fibrosis showed significant differences in HDL-bound protein levels; this translated into increased cardiovascular risk based on pCAD index. Different lipoprotein composition and function may explain the link between liver disease and increased cardiovascular mortality in these patients.

Prevalence, characteristics, and respiratory arousal threshold of positional obstructive sleep apnea in China: a large scale study from Shanghai Sleep Health Study cohort.

PURPOSE: To evaluate the prevalence, characteristics, and respiratory arousal threshold (ArTH) of Chinese patients with positional obstructive sleep apnea (POSA) according to the Cartwright Classification (CC) and Amsterdam Positional Obstructive Sleep Apnea Classification (APOC). METHODS: A large-scale cross-sectional study was conducted in our sleep center from 2007 to 2018 to analyze the clinical and polysomnography (PSG) data of Chinese POSA patients. Low ArTH was defined based on PSG indices. RESULTS: Of 5,748 OSA patients, 36.80% met the CC criteria, and 42.88% the APOC criteria, for POSA. The prevalence of POSA was significantly higher in women than men (40.21% and 46.52% vs. 36.13% and 42.18% for CC and APOC, respectively). Chinese POSA patients had a lower apnea hypopnea index (AHI) and lower oxygen desaturation index, shorter duration of oxygen saturation (SaO2) < 90%, and a higher mean SaO2 and higher lowest SaO2 value compared to subjects with non-positional OSA (NPOSA). More than 40% of the POSA patients had a low ArTH; the proportion was extremely high in the supine-isolated-POSA (si-POSA) group and APOC I group. In multivariate logistic regression analyses, higher mean SaO2 and lower AHI during sleep were positive predictors of POSA. CONCLUSIONS: According to the CC and APOC criteria, more than 1/3 of our Chinese subjects with OSA had POSA. Chinese POSA patients had less severe OSA and nocturnal hypoxia. Compared to NPOSA patients, significantly more patients with POSA had a low ArTH. A low ArTH may be an important endotype in the pathogenesis of POSA, especially in patients with si-POSA and APOC I. Further studies are necessary to develop personalized management strategies for POSA patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry; URL: http://www.chictr.org.cn ; No. ChiCTR1900025714 (retrospectively registered).

Advanced partial occlusion controller allows for increased precision during targeted regional optimization in a porcine model of hemorrhagic shock.

BACKGROUND: Targeted regional optimization (TRO), a partial resuscitative endovascular balloon occlusion of the aorta strategy, may mitigate distal ischemia and extend the window of effectiveness for this adjunct. An automated device may allow greater control and precise regulation of flow past the balloon, while being less resource-intensive. The objective of this study was to assess the technical feasibility of the novel advanced partial occlusion controller (APOC) in achieving TRO at multiple distal pressures. METHODS: Female swine (n = 48, 68.1 ± 0.7 kg) were randomized to a target distal mean arterial pressure (MAP) of 25 mm Hg, 35 mm Hg, or 45 mm Hg by either manual (MAN) or APOC regulation (n = 8 per group). Uncontrolled hemorrhage was generated by liver laceration. Targeted regional optimization was performed for 85 minutes, followed by surgical control and a 6-hour critical care phase. Proximal and distal MAP and flow rates were measured continuously. RESULTS: At a target distal MAP of 25 mm Hg, there was no difference in the MAP attained (APOC: 26.2 ± 1.05 vs. MAN: 26.1 ± 1.78 mm Hg) but the APOC had significantly less deviance (10.9%) than manual titration (14.9%, p < 0.0001). Similarly, at a target distal MAP of 45 mm Hg, there was no difference in mean pressure (44.0 ± 0.900 mm Hg vs. 45.2 ± 1.31 mm Hg) but APOC had less deviance (9.34% vs. 11.9%, p < 0.0001). There was no difference between APOC and MAN in mean (34.6 mm Hg vs. 33.7 mm Hg) or deviance (9.95% vs. 10.4%) at a target distal MAP of 35 mm Hg, respectively. The APOC made on average 77 balloon volume adjustments per experiment compared with 29 by manual titrations. CONCLUSION: The novel APOC consistently achieved and sustained precisely regulated TRO across all groups and demonstrated reduced deviance at the 25 mm Hg and 45 mm Hg groups compared with manual titration.

Is Apo-CIII the new cardiovascular target? An analysis of its current clinical and dietetic therapies.

AIMS: Recently, Apolipoprotein CIII (Apo-CIII) has gained remarkable attention since its overexpression has been strongly correlated to cardiovascular disease (CVD) occurrence. The aim of this review was to summarize the latest findings of Apo-CIII as a CVDs and diabetes risk factor, as well as the plausible mechanisms involved in the development of these pathologies, with particular emphasis on current clinical and dietetic therapies. DATA SYNTHESIS: Apo-CIII is a small protein (∼8.8 kDa) that, among other functions, inhibits lipoprotein lipase, a key enzyme in lipid metabolism. Apo-CIII plays a fundamental role in the physiopathology of atherosclerosis, type-1, and type-2 diabetes. Apo-CIII has become a potential clinical target to tackle these multifactorial diseases. Dietetic (omega-3 fatty acids, stanols, polyphenols, lycopene) and non-dietetic (fibrates, statins, and antisense oligonucleotides) therapies have shown promising results to regulate Apo-CIII and triglyceride levels. However, more information from clinical trials is required to validate it as a new target for atherosclerosis and diabetes types 1 and 2. CONCLUSIONS: There are still several pathways involving Apo-CIII regulation that might be affected by bioactive compounds that need further research. The mechanisms that trigger metabolic responses following bioactive compounds consumption are mainly related to higher LPL expression and PPARα activation, although the complete pathways are yet to be elucidated.

Apolipoprotein CIII predicts cardiovascular events in patients with coronary artery disease: a prospective observational study.

BACKGROUND: Apolipoprotein CIII (apoCIII) is associated with triglyceride-rich lipoprotein metabolism and has emerged as independent marker for risk of cardiovascular disease. The objective was to test whether apoCIII is regulated postprandially and whether apoCIII concentrations in native and chylomicron-free serum predict future cardiovascular events in patients with stable coronary artery disease (CAD). METHODS: ApoCIII concentrations were measured in native and chylomicron-free serum in the fasting state and after a standardized oral fat load test in 195 patients with stable CAD. Clinical follow-up was 48 months. Chylomicron-free serum was prepared by ultracentrifugation (18,000 rpm, 3 h). The log-rank test and Cox regression analyses were used to investigate the association of apoCIII with recurrent cardiovascular events. RESULTS: Of the 195 patients included, 92 had a cardiovascular event, and 103 did not. 97% were treated with a statin. No significant changes in apoCIII concentration were observed after the oral fat load test. The apoCIII concentration was associated with event-free survival independent of conventional risk factors. This association reached statistical significance only for apoCIII concentration measured in chylomicron-free serum (hazard ratio [95% confidence interval] for apoCIII above the mean: postprandial: 1.67 (1.06-2.29), P = 0.028, fasting: 2.09 (1.32-3.32), P = 0.002), but not for apoCIII concentration measured in native serum (postprandial: 1.47 [0.89-2.43], P = 0.133, fasting: 1.56 [0.95-2.58], P = 0.081). The effects were independent of other risk factors. CONCLUSIONS: ApoCIII concentrations in chylomicron-free serum are independently associated with event-free survival in patients with CAD both in fasting and postprandial state. This findings support considering apoCIII for risk assessment and attempting to test the hypothesis that lowering apoCIII reduces residual cardiovascular risk. TAKE HOME MESSAGE: Apolipoprotein CIII concentration measured in chylomicron-free serum predicts recurrent cardiovascular events in patients with stable coronary artery disease. TRIAL REGISTRATION: The trial which included the participants of this study was registered at https://clinicaltrials.gov (NCT00628524) on March 5, 2008.

Non-coding variability at the APOE locus contributes to the Alzheimer's risk.

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.

Diagnostic and prognostic significance of mRNA expressions of apolipoprotein A and C family genes in hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most common and lethal malignancies worldwide. Apolipoproteins (APOs) have been reported increasingly for their relationships with tumors. We aim at exploring the potential relationships of apolipoprotein A (APOA) and apolipoprotein C (APOC) family members with HCC. METHODS: A data set, containing 212 hepatitis B virus-related HCC patients, was used for analysis. The diagnostic and prognostic ability of APOA and APOC family genes was figured out. Risk score models and nomograms were developed for the HCC prognosis prediction. Moreover, molecular mechanism exploration were identified biological processes and metabolic pathways of these genes involved in. Validation analysis was carried out using online website. RESULTS: APOA1, APOC1, APOC3, and APOC4 showed robust diagnosis significance (all P < 0.05). APOA4, APOC3, and APOC4 were associated with the overall survival (OS) while APOA4 and APOC4 were linked to recurrence-free survival (RFS, all P ≤ 0.05). Risk score models and nomograms had the advantage of predicting OS and RFS for HCC. Molecular mechanism exploration indicated that these genes were involved in the steroid metabolic process, the PPAR signaling pathway, and fatty acid metabolism. Besides that, validation analysis revealed that APOC1 and APOC4 had an association with OS; and APOC3 was associated with OS and RFS (all P ≤ 0.05). CONCLUSIONS: APOA1, APOC1, APOC3, and APOC4 are likely to be potential diagnostic biomarkers and APOC3 and APOC4 are likely to be potential prognostic biomarkers for hepatitis B virus-related HCC. They may be involved in the steroid metabolic process, PPAR signaling pathway, and fatty acid metabolism.

Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups.

The apolipoprotein E-C1-C4-C2 gene cluster at 19q13.32 encodes four amphipathic apolipoproteins. The influence of APOE common polymorphisms on plasma lipid/lipoprotein profile, especially on LDL-related traits, is well recognized; however, little is known about the role of other genes/variants in this gene cluster. In this study, we evaluated the role of common and uncommon/rare genetic variation in this gene region on inter-individual variation in plasma lipoprotein levels in non-Hispanic Whites (NHWs) and African blacks (ABs). In the variant discovery step, the APOE, APOC1, APOC4, APOC2 genes were sequenced along with their flanking and hepatic control regions (HCR1 and HCR2) in 190 subjects with extreme HDL-C/TG levels. The next step involved the genotyping of 623 NHWs and 788 ABs for the identified uncommon/rare variants and common tagSNPs along with additional relevant SNPs selected from public resources, followed by association analyses with lipid traits. A total of 230 sequence variants, including 15 indels were identified, of which 65 were novel. A total of 70 QC-passed variants in NHWs and 108 QC-passed variants in ABs were included in the final association analyses. Single-site association analysis of SNPs with MAF>1% revealed 20 variants in NHWs and 24 variants in ABs showing evidence of association with at least one lipid trait, including several variants exhibiting independent associations from the established APOE polymorphism even after multiple-testing correction. Overall, our study has confirmed known associations and also identified novel associations in this genomic region with various lipid traits. Our data also support the contribution of both common and uncommon/rare variation in this gene region in affecting plasma lipid profile in the general population.

Molecular regulation of plasma lipid levels during systemic inflammation and sepsis.

PURPOSE OF REVIEW: Sepsis is a common syndrome of multiorgan system dysfunction caused by a dysregulated inflammatory response to an infection and is associated with high rates of mortality. Plasma lipid and lipoprotein levels and composition change profoundly during sepsis and have emerged as both biomarkers and potential therapeutic targets for this condition. The purpose of this article is to review recent progress in the understanding of the molecular regulation of lipid metabolism during sepsis. RECENT FINDINGS: Patients who experience greater declines in high-density lipoprotein during sepsis are at much greater risk of succumbing to organ failure and death. Although the causality of these findings remains unclear, all lipoprotein classes can sequester and prevent the excessive inflammation caused by pathogen-associated lipids during severe infections such as sepsis. This primordial innate immune function has been best characterized for high-density lipoproteins. Most importantly, results from human genetics and preclinical animal studies have suggested that several lipid treatment strategies, initially designed for atherosclerosis, may hold promise as therapies for sepsis. SUMMARY: Lipid and lipoprotein metabolism undergoes significant changes during sepsis. An improved understanding of the molecular regulation of these changes may lead to new opportunities for the treatment of sepsis.

Variants at the APOE /C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High-Density Lipoprotein Cholesterol.

Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans. Methods and Results We measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome-wide significant signals ( P<6.25×10-9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology ( CETP , LIPC , LPL , APOA 1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE /C1/C2/C4 variant ( rs141622900, P nonadjusted=1.0×10-11; P adjusted=8.8×10-9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP 1 CB / PLB 1 and RBFOX 3/ ENPP 7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome-wide association study . These analyses identified 27 significant CEC associations, implicating 5 additional loci ( GCKR , LIPG , PLTP , PPARA , and TRIB 1). Conclusions Our genome-wide association study identified common genetic variation at the APOE /C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL -based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.

Novel Therapeutic Targets for Managing Dyslipidemia.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified. These targets may provide additional avenues to prevent and treat atherosclerotic disease. We therefore review these novel molecular targets by addressing available Mendelian and observational data, therapeutic agents in development, and early outcomes results.

Impact of Novel Low-Density Lipoprotein-Cholesterol Assessment on the Utility of Secondary Non-High-Density Lipoprotein-C and Apolipoprotein B Targets in Selected Worldwide Dyslipidemia Guidelines.

BACKGROUND: Selected dyslipidemia guidelines recommend non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (apoB) as secondary targets to the primary target of low-density lipoprotein-cholesterol (LDL-C). After considering 2 LDL-C estimates that differ in accuracy, we examined: (1) how frequently non-HDL-C guideline targets could change management; and (2) the utility of apoB targets after meeting LDL-C and non-HDL-C targets. METHODS: We analyzed 2518 adults representative of the US population from the 2011 to 2012 National Health and Nutrition Examination Survey and 126 092 patients from the Very Large Database of Lipids study with apoB. We identified all individuals as well as those with high-risk clinical features, including coronary artery disease, diabetes mellitus, and metabolic syndrome who met very high- and high-risk guideline targets of LDL-C <70 and <100 mg/dL using Friedewald estimation (LDL-CF) and a novel, more accurate method (LDL-CN). Next, we examined those not meeting non-HDL-C (<100, <130 mg/dL) and apoB (<80, <100 mg/dL) guideline targets. In those meeting dual LDL-C and non-HDL-C targets (<70 and <100 mg/dL, respectively, or <100 and <130 mg/dL, respectively), we determined the proportion of individuals who did not meet guideline apoB targets (<80 or <100 mg/dL). RESULTS: A total of 7% to 9% and 31% to 36% of individuals had LDL-C <70 and <100 mg/dL, respectively. Among those with LDL-CF<70 mg/dL, 14% to 15% had non-HDL-C ≥100 mg/dL, and 7% to 8% had apoB ≥80 mg/dL. Among those with LDL-CF<100 mg/dL, 8% to 10% had non-HDL-C ≥130 mg/dL and 2% to 3% had apoB ≥100 mg/dL. In comparison, among those with LDL-CN<70 or 100 mg/dL, only ≈2% and ≈1% of individuals, respectively, had non-HDL-C and apoB values above guideline targets. Similar trends were upheld among those with high-risk clinical features: ≈0% to 3% of individuals with LDL-CN<70 mg/dL had non-HDL-C ≥100 mg/dL or apoB ≥80 mg/dL compared with 13% to 38% and 9% to 25%, respectively, in those with LDL-CF<70 mg/dL. With LDL-CF or LDL-CN<70 mg/dL and non-HDL-C <100 mg/dL, 0% to 1% had apoB ≥80 mg/dL. Among all dual LDL-CF or LDL-CN<100 mg/dL and non-HDL-C <130 mg/dL individuals, 0% to 0.4% had apoB ≥100 mg/dL. These findings were robust to sex, fasting status, and lipid-lowering therapy status. CONCLUSIONS: After more accurately estimating LDL-C, guideline-suggested non-HDL-C targets could alter management in only a small fraction of individuals, including those with coronary artery disease and other high-risk clinical features. Furthermore, current guideline-suggested apoB targets provide modest utility after meeting cholesterol targets. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489.