Apolipoprotein B Research Articles

Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY-n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection.

SARS-CoV-2 infection causes a significant reduction in lipoprotein-bound serum phospholipids give rise to supramolecular phospholipid composite (SPC) signals observed in diffusion and relaxation edited 1H NMR spectra. To characterize the chemical structural components and compartmental location of SPC and to understand further its possible diagnostic properties, we applied a Statistical HeterospectroscopY in n-dimensions (SHY-n) approach. This involved statistically linking a series of orthogonal measurements made on the same samples, using independent analytical techniques and instruments, to identify the major individual phospholipid components giving rise to the SPC signals. Thus, an integrated model for SARS-CoV-2 positive and control adults is presented that relates three identified diagnostic subregions of the SPC signal envelope (SPC1, SPC2, and SPC3) generated using diffusion and relaxation edited (DIRE) NMR spectroscopy to lipoprotein and lipid measurements obtained by in vitro diagnostic NMR spectroscopy and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The SPC signals were then correlated sequentially with (a) total phospholipids in lipoprotein subfractions; (b) apolipoproteins B100, A1, and A2 in different lipoproteins and subcompartments; and (c) MS-measured total serum phosphatidylcholines present in the NMR detection range (i.e., PCs: 16.0,18.2; 18.0,18.1; 18.2,18.2; 16.0,18.1; 16.0,20.4; 18.0,18.2; 18.1,18.2), lysophosphatidylcholines (LPCs: 16.0 and 18.2), and sphingomyelin (SM 22.1). The SPC3/SPC2 ratio correlated strongly (r = 0.86) with the apolipoprotein B100/A1 ratio, a well-established marker of cardiovascular disease risk that is markedly elevated during acute SARS-CoV-2 infection. These data indicate the considerable potential of using a serum SPC measurement as a metric of cardiovascular risk based on a single NMR experiment. This is of specific interest in relation to understanding the potential for increased cardiovascular risk in COVID-19 patients and risk persistence in post-acute COVID-19 syndrome (PACS).

Effects of Hazelnut Consumption on Cardiometabolic Risk Factors and Acceptance: A Systematic Review.

Despite being rich sources of monounsaturated fat and a number of vitamins, minerals, and phytonutrients, hazelnuts have received less attention than some other nut types. A qualitative systematic review was carried out to determine the effects of hazelnut consumption on acceptance and markers of cardiometabolic health, including blood lipids and lipoproteins, apolipoproteins A1 and B100, body weight and composition, blood pressure, glycemia, antioxidant status, oxidative stress, inflammation, and endothelial function. In total, 22 intervention studies (25 publications) met our inclusion criteria. The findings indicate some improvements in cardiometabolic risk factors; however, limitations in study design mean interpretation is problematic. The inclusion of hazelnuts in the diet did not adversely affect body weight and composition. Acceptance of hazelnuts remained stable over time confirming nut consumption guidelines are feasible and sustainable. Future studies using more robust study designs in a variety of populations are required to draw more definitive conclusions on the health benefits of hazelnut consumption.

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters.

Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center. Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed. Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms. Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.

Sequencing the Exon.4 of the LDL Receptor Gene in Patients with Familial Hypercholesterolemia in the Population of Bushehr, Southwestern Iran: the Possible New Mutations

Background & Objective: Familial hypercholesterolemia (FH) is the most common genetic disease in the world and an autosomal dominant disease characterized by increased plasma cholesterol and low-density lipoprotein (LDL) concentrations. The clinical diagnosis of the disease is based on family history, the findings of medical examinations, and the measurement of cholesterol levels. The most important cause of FH is the mutation in one of the LDL-R, APOB, and PSCK9 genes. About 90% of mutations occur in the LDL-R gene, which accounts for a total of 2,000 different mutations. Different types of mutations have been observed on different exons of the LDL-R gene, but most of the mutations have been reported on Exon 4. The aim of this study was to sequence and analyze Exon 4 in patients with familial hypercholesterolemia in Bushehr province in Iran. Materials & Methods: In this study, 32 patients were selected based on global criteria for diagnosing the disease, and a portion of LDL-R containing complete sequence of exon 4 was amplified using LDLRE4F1/ LDLRE4R1 Primers and blood genomic DNA as a template. PCR products were sequenced and compared with reference sequence to find probable muta­tions. Results: The results of sequencing and comparison with the reference sequence showed that no mutation was found in the exon 4 LDL-R gene. Therefore, this exon did not play a role in FH in the population under study. Conclusion: Therefore, the cause of FH may be due to the mutations in other areas of the LDL-R gene or other genes, such as APOB and PSCK9.

Role of diacylglycerol O-acyltransferase (DGAT) isoforms in bovine hepatic fatty acid metabolism

Fatty acid accumulation in hepatocytes induced by high concentrations of fatty acids due to lipolysis and the associated oxidative damage they cause occur most frequently after calving. Because of their role in esterification of fatty acids, diacylglycerol acyltransferase isoforms (DGAT1 and DGAT2) could play a role in the susceptibility of dairy cows to develop fatty liver. To gain mechanistic insights, we performed in vivo and in vitro analyses using liver biopsies or isolated primary hepatocytes. The in vivo study (n = 5 cows/group) involved healthy cows [average liver triacylglycerol (TAG) = 0.78%; 0.58 to 0.93%, ratio of triglyceride weight to wet liver weight] or cows diagnosed with fatty liver (average TAG = 7.60%; 5.31 to 10.54%). In vitro, hepatocytes isolated from 3 healthy female calves (1 d old, 44 to 53 kg) were challenged with (fatty acids) or without (control) a 1.2 mM mixture of fatty acids in an attempt to induce metabolic stress. Furthermore, hepatocytes were treated with DGAT1 inhibitor or DGAT2 inhibitor for 2 h followed by a challenge with (DGAT1 inhibitor + fatty acids or DGAT2 inhibitor + fatty acids) or without (DGAT1 inhibitor or DGAT2 inhibitor) the 1.2 mM mixture of fatty acids for 12 h. Data analysis of liver biopsies was compared using a 2-tailed unpaired Student's t-test. Data from calf hepatocyte treatment comparisons were assessed by one-way ANOVA, and multiplicity for each experiment was adjusted by the Holm's procedure. Data indicated that both fatty liver and in vitro challenge with fatty acids were associated with greater mRNA and protein abundance of SREBF1, FASN, DGAT1, and DGAT2. In contrast, mRNA and protein abundance of CPT1A and very low-density lipoprotein synthesis-related proteins MTTP and APOB were markedly lower. However, compared with fatty acid challenge alone, DGAT1 inhibitor + fatty acids led to greater mRNA and protein abundance of CPT1A and APOB, and greater mRNA abundance of SREBF1 and MTTP. Furthermore, this treatment led to lower mRNA abundance of FASN and DGAT2 and TAG concentrations. Compared with fatty acid challenge alone, DGAT2 inhibitor + fatty acids led to greater mRNA and protein abundance of CPT1A, MTTP, and APOB, and lower mRNA and protein abundance of SREBF1 and FASN. In addition, compared with control and fatty acids, there was greater protein abundance of GRP78 and PERK in both DGAT1 and DGAT2 inhibitor with or without fatty acids. Furthermore, compared with control and fatty acids, reactive oxygen species concentrations in the DGAT1 inhibitor with or without fatty acid group was greater. Overall, data suggested that DGAT1 is particularly relevant in the context of hepatocyte TAG synthesis from exogenous fatty acids. Disruption of both DGAT1 and DGAT2 altered lipid homeostasis, channeling fatty acids toward oxidation and generation of reactive oxygen species. Both DGAT isoforms play a role in promoting fatty acid storage into TAG and lipid droplets to protect hepatocytes from oxidative damage.

Methionine-Mediated Regulation of Intestinal Structure and Lipid Transport in the Rice Field Eel (Monopterus albus)

An eight-week feeding trial discusses how methionine affects intestinal barrier and lipid transport on rice field eel (Monopterus albus). Six isoenergetic and isonitrogenous feeds contained different levels of methionine (0, 2 g/kg, 4 g/kg, 6 g/kg, 8 g/kg, or 10 g/kg). Compared with M0 (0 g/kg), gastric amylase, lipase, and trypsin were remarkably increased as dietary methionine ( P < 0.05 ); intestinal amylase, lipase, and trypsin were remarkably increased in M8 (8 g/kg) ( P < 0.05 ). Compared with M0, gastric fovea was remarkably increased ( P < 0.001 ), gastric epithelium is neater in M8 than that in M0, intestinal villus height and muscular thickness are remarkably increased in M8 ( P < 0.001 ), and amounts of goblet cells per root in M8 were increased ( P > 0.05 ), while intestinal crypt depth was markedly decreased ( P < 0.001 ). Lipid droplets in the intestinal villus and mucosal layer in the M8 (8 g/kg) group were more than that in M0 (0 g/kg). Compared with M0 (0 g/kg), the intestinal gcn2 and eif2α were downregulated in M8 (8 g/kg) ( P < 0.01 and P < 0.05 , respectively), while occ, cl12, cl15, zo-1, zo-2, hdlbp, ldlrap, npc1l1, cd36, fatp1, fatp2, fatp6, apo, apoa, apob, apoc, apoe, mct1, mct2, mct8, lpl, mttp, moat2, and dgat2 were upregulated markedly in M8 (8 g/kg). Intestinal eif2α expression was positively correlated with gcn2, and intestinal zo-1, cl15, fatp6, ldlrap, mct2, mct8, apo, apob, mct1, apoc, fatp1, mttp, cd36, occ, npc1l1, hdlbp, fatp2, apoe, lpl, and moat2 gene expression was negatively correlated with gcn2. In conclusion, methionine deficiency affected the gastric and intestinal structures, damaged the intestinal barrier, and decreased lipid and fatty acid transport. Besides, gcn2 could be activated when M. albus was fed methionine-deficient feed.

Exploring the Pattern of Metabolic Alterations Causing Energy Imbalance via PPARα Dysregulation in Cardiac Muscle During Doxorubicin Treatment.

Cardiotoxicity by anthracycline antineoplastic drug doxorubicin is one of the systemic toxicity of the cardiovascular system. The mechanism responsible for doxorubicin cardiotoxicity and lipid metabolism remains elusive. The current study tested the hypotheses that the role of peroxisome proliferator-activated receptor α (PPARα) in the progress of doxorubicin-induced cardiomyopathy and its mechanism behind lipid metabolism. In the present study, male rats were subjected to intraperitoneal injection (5-week period) of doxorubicin with different dosages such as low dosage (1.5mg/kg body weight) and high dosage (15mg/kg body weight) to induce doxorubicin cardiomyopathy. Myocardial PPARα was impaired in both low dosage and high dosage of doxorubicin-treated rats in a dose-dependent manner. The attenuated level of PPARα impairs the expression of the genes involved in mitochondrial transporter, fatty acid transportation, lipolysis, lipid metabolism, and fatty acid oxidation. Moreover, it disturbs the reverse triacylglycerol transporter apolipoprotein B-100 (APOB) in the myocardium. Doxorubicin elevates the circulatory lipid profile and glucose. Further aggravated lipid profile in circulation impedes the metabolism of lipid in cardiac tissue, which causes a lipotoxic condition in the heart and subsequently associated disease for the period of doxorubicin treatment. Elevated lipids in the circulation translocate into the heart dysregulates lipid metabolism in the heart, which causes augmented oxidative stress and necro-apoptosis and mediates lipotoxic conditions. This finding determines the mechanistic role of doxorubicin-disturbed lipid metabolism via PPARα, which leads to cardiac dysfunction.

Forty year follow-up of three patients with complete absence of apolipoprotein B-containing lipoproteins

Complete deficiency of apolipoprotein (apo) B-containing lipoproteins can result from both abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HoHBL), caused by bi-allelic loss-of-function variants in the MTTP and APOB genes encoding microsomal triglyceride transfer protein and apolipoprotein (apo) B, respectively. Both conditions are associated with failure to assemble and secrete apo B-containing lipoproteins from intestine and liver, resulting in absence of chylomicrons, very low-density lipoproteins and remnants, and low-density lipoproteins. Because absorption and transport of fat soluble vitamins requires intact production of apo B-containing lipoproteins, untreated patients develop fat soluble vitamin deficiencies, with associated clinical features including atypical retinitis pigmentosa, osteopenia, neuromyopathy and coagulopathy. Other features include acanthocytosis on the peripheral blood film, fat malabsorption and hepatosteatosis. We describe two patients with ABL and one with HoHBL who have each been on high dose oral fat soluble vitamin replacement under the care of the same physician for more than four decades. Each patient has remained clinically stable. A recent liver biopsy from an ABL patient showed mild macrovesicular steatosis, patchy microvesicular steatosis and mild fibrosis. These observations add to our understanding of the long term trajectory of ABL and HoHBL, and emphasize the importance of compliance to treatment and follow up.

Ionizable liposomal siRNA therapeutics enables potent and persistent treatment of Hepatitis B

Small interfering RNA (siRNA) constitutes a promising therapeutic modality supporting the potential functional cure of hepatitis B. A novel ionizable lipidoid nanoparticle (RBP131) and a state-of-the-art lyophilization technology were developed in this study, enabling to deliver siRNA targeting apolipoprotein B (APOB) into the hepatocytes with an ED50 of 0.05 mg/kg after intravenous injection. In addition, according to the requirements of Investigational New Drug (IND) application, a potent siRNA targeting hepatitis B virus (HBV) was selected and encapsulated with RBP131 to fabricate a therapeutic formulation termed RB-HBV008. Efficacy investigations in transient and transgenic mouse models revealed that the expressions of viral RNAs and antigens (HBsAg and HBeAg), as well as viral DNA, were repressed, dose-dependently and time-dependently at multilog decreasing amplitude, in both circulation and liver tissue. In contrast, entecavir (ETV), the first-line clinically-employed nucleoside analog drug, barely recused the antigen expression, although it triggered as high as 3.50 log reduction of viral DNA, in line with clinical observations. Moreover, the toxicity profiles suggested satisfactory safety outcomes with ten times the therapeutic window. Therefore, this study provides an effective nucleic acid delivery system and a promising RNAi agent for the treatment of hepatitis B.

"Evaluation of Biliary Cholesterol, Biliary Ferritin and Expression of Apo B-100 Gene in Patients of Cholelithiasis"

Chinmay Bagla1*, Vivek Agrawal2 and B D Banerjee3 Author Affiliations 1PG Resident, Department of Surgery, UCMS & GTB Hospital, India 2Director Professor, Department of Surgery, UCMS & GTB Hospital, India 3Professor, Department of Biochemistry, UCMS & GTB Hospital, India Received: February 03, 2022 | Published: February 10, 2022 Corresponding author: Chinmay Bagla, PG Resident, Department of Surgery, UCMS & GTB Hospital, New Delhi, India DOI: 10.26717/BJSTR.2022.41.006659

Posttranslational modifications of proteins are key features in the identification of CSF biomarkers of multiple sclerosis

BackgroundMultiple sclerosis is an inflammatory and degenerative disease of the central nervous system (CNS) characterized by demyelination and concomitant axonal loss. The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance. Herein, we compared the cerebrospinal fluid (CSF) proteome of patients with multiple sclerosis (in the relapse–remitting phase of the disease) and other diseases of the CNS (inflammatory and non-inflammatory) aiming at identifying reliable biomarkers of multiple sclerosis.MethodsCSF samples from the discovery group were resolved by 2D-gel electrophoresis followed by identification of the protein spots by mass spectrometry. The results were analyzed using univariate (Student’s t test) and multivariate (Hierarchical Cluster Analysis, Principal Component Analysis, Linear Discriminant Analysis) statistical and numerical techniques, to identify a set of protein spots that were differentially expressed in CSF samples from patients with multiple sclerosis when compared with other two groups. Validation of the results was performed in samples from a different set of patients using quantitative (e.g., ELISA) and semi-quantitative (e.g., Western Blot) experimental approaches.ResultsAnalysis of the 2D-gels showed 13 protein spots that were differentially expressed in the three groups of patients: Alpha-1-antichymotrypsin, Prostaglandin-H2-isomerase, Retinol binding protein 4, Transthyretin (TTR), Apolipoprotein E, Gelsolin, Angiotensinogen, Agrin, Serum albumin, Myosin-15, Apolipoprotein B-100 and EF-hand calcium-binding domain—containing protein. ELISA experiments allowed validating part of the results obtained in the proteomics analysis and showed that some of the alterations in the CSF proteome are also mirrored in serum samples from multiple sclerosis patients. CSF of multiple sclerosis patients was characterized by TTR oligomerization, thus highlighting the importance of analyzing posttranslational modifications of the proteome in the identification of novel biomarkers of the disease.ConclusionsThe model built based on the results obtained upon analysis of the 2D-gels and in the validation phase attained an accuracy of about 80% in distinguishing multiple sclerosis patients and the other two groups.

Schisandrae Fructus oil-induced elevation in serum triglyceride and lipoprotein concentrations associated with physiologic hepatomegaly in mice

Objective: To investigate hypertriglyceridemia and hepatomegaly caused by Schisandrae Sphenantherae Fructus (FSS) and Schisandra chinensis Fructus (FSC) oils in mice. Methods: Mice were orally administered a single dose of Schisandrae Fructus oils. Serum and hepatic triglyceride (TG), triglyceride transfer protein (TTP), apolipoprotein B48 (Apo B48), very-low-density lipoprotein (VLDL), hepatocyte growth factor (HGF), alanine aminotransfease (ALT) and liver index were measured at 6-120 h post-dosing. Results: FSS and FSC oil caused time and dose-dependent increases in serum and hepatic TG levels, with maximum increases in the liver (by 297% and 340%) at 12 h post-dosing and serum (244% and 439%) at 24-h post-dosing, respectively. Schisandrae Fructus oil treatments also elevated the levels of serum TTP by 51% and 63%, Apo B48 by 152% and 425%, and VLDL by 67% and 38% in mice, respectively. FSS and FSC oil treatments also increased liver mass by 53% and 55% and HGF by 106% and 174%, but lowered serum ALT activity by 38% and 22%, respectively. Fenofibrate pre/ co-treatment attenuated the FSS and FSC oil-induced elevation in serum TG levels by 41% and 49% at 48 h post-dosing, respectively, but increased hepatic TG contents (by 38% and 33%, respectively) at 12 h post-dosing. Conclusions: Our findings provide evidence to support the establishment of a novel mouse model of hypertriglyceridemia by oral administration of FSS oil (mainly increasing endogenous TG) and FSC oil (mainly elevating exogenous TG).

ApoB could be best predictor of future MI risk

Apoprotein B (ApoB) was the only lipid parameter significantly associated with an increased risk of myocardial infarction (MI), according to results of a prospective cohort analysis presented at the 2021 American Heart Association (AHA) Scientific Sessions and published simultaneously in JAMA Cardiology. “We all know that cardiovascular disease has a link to cholesterol and cholesterol-containing compounds or particles,” said Manesh Raman Patel, MD, chief of cardiology and clinical pharmacology at Duke University in an interview with JAMA Medical News. “We traditionally haven’t used [ApoB] in clinical practice probably because we haven’t had therapies that have pushed that measure itself down, although some might be coming. So that was the key finding [from this study] to start to get our clinicians ready for therapies and predictors tied to ApoB.” ApoBs are atherogenic proteins found in lipoprotein particles. Since each of these particles has one ApoB molecule, measuring ApoB levels in fasting blood gives a good approximation of the total number of atherogenic lipoproteins in the blood. Examples of ApoB-containing lipoprotein particles include chylomicrons and low-, intermediate-, and very low-density lipoproteins. The greater the number, the greater the risk of a cardiovascular event. When compared to ApoB, which is a surrogate for the number of atherogenic particles, LDL cholesterol is a surrogate for the cholesterol concentration of the LDL particle. LDL cholesterol has long been the standard lipid marker for cardiovascular risk and the primary target of cholesterol-lowering therapies. Treatment guidelines have also focused on optimal LDL goals. There are scenarios, however, in which assessment of LDL cholesterol may underestimate the concentration, such as in patients with hypertriglyceridemia, diabetes, or those who are obese. In its 2018 lipid guidelines, the American College of Cardiology and AHA commented on ApoB levels and highlighted its association with cardiovascular disease. The guidelines stated that under certain circumstances, particularly in patients with hypertriglyceridemia, the measurement of ApoB may be advantageous. However, ApoB measurement carries an extra cost and its measurement in some laboratories may not be reliable. The 2019 European Society of Cardiology and the European Atherosclerosis Society lipid guidelines state that ApoB analysis is recommended for risk assessment, particularly in those with hypertriglyceridemia, diabetes, obesity or metabolic syndrome, or VLDL cholesterol levels. They note that it can be used as an alternative to LDL, if available, as the primary measurement for screening, diagnosis, and management, and may be preferred over non-HDL cholesterol in people with hypertriglyceridemia, diabetes, obesity, or VLDL. In an accompanying commentary to the JAMA Cardiology study, the authors write: “ApoB should be the primary measure of the atherogenic risk of the ApoB lipoproteins and the primary measure of the adequacy of therapy to lower the ApoB lipoproteins.” They note it can be used in combination with a conventional lipid panel to allow for an accurate diagnosis of all clinically significant lipid disorders. In their view, the debate on ApoB versus LDL and non-HDL cholesterol is over. The prospective cohort analysis was conducted using data from the UK Biobank and two interventional studies. A total of 389,529 patients who were not receiving lipid-lowering therapy (primary prevention cohort) were included from the UK Biobank, and 40,430 patients with established atherosclerosis disease who were receiving lipid-lowering therapy (secondary prevention cohort) were included from the two studies. The researchers used two models to calculate MI risk: a clinically adjusted model (i.e., for age, sex, BMI, smoking status, hypertension, diabetes, ethnicity, and kidney function, as well as prior MI, stroke, and peripheral artery disease for the secondary prevention cohort) and a model that was both clinically and lipid adjusted (i.e., ApoB, non-HDL, triglycerides, and HDL). In the primary prevention cohort, when adjusted clinically, increases in ApoB, non-HDL cholesterol, and triglycerides were all associated with an increased risk of MI, but once lipid parameters were also adjusted, only increases in ApoB remained significantly associated with an increased risk of MI. Similar results were seen in the secondary prevention cohort, with the clinically adjusted model showing increases in ApoB and non-HDL cholesterol associated with an increased risk of MI, and only increases in ApoB remaining significant once lipids were adjusted as well.

Familial Hypercholesterolemia: Update and Review.

Knowledge of epidemiology, genetic etiopathogenesis, diagnostic criteria, and management of familial hypercholesterolemia have increased in the last two decades. Several population studies have shown that familial hypercholesterolemia is more frequent than previously thought, making this entity the most common metabolic disease with monogenic inheritance in the world. Identification of causal heterozygous pathogenic variants in LDLR, APOB, and PCSK9 genes has increased diagnostic accuracy of classical criteria (extreme hypercholesterolemia, personal / family history of premature coronary artery disease or other cardiovascular diseases). Genetic screening has been recently introduced in many European countries to detect patients with familial hypercholesterolemia, mainly affected pediatric subjects, asymptomatic or those at the beggining of their disease, to increase surveillance and avoid complications such as cardiovascular diseases. Cholesterol- lowering drugs should be started as soon as the diagnosis is made. Various combinations between drugs can be used when the goal is not achieved. New therapies, including small interference ribonucleic acids (siRNA) are being tested in different clinical trials.

Mipomersen in Familial Hypercholesterolemia: An Update on Health-Related Quality of Life and Patient-Reported Outcomes.

Familial hypercholesterolemia (FH) is an autosomal dominant condition that leads to significantly elevated low-density lipoprotein cholesterol (LDL-C) levels and an elevated risk for cardiovascular disease. Mipomersen is an antisense oligonucleotide inhibitor targeted to apolipoprotein B-100 (apoB-100) mRNA that is administered via subcutaneous injection. Once administered, mipomersen causes selective degradation of the apoB-100 mRNA and inhibition of protein translation. This ultimately results in substantial reductions in LDL-C and other lipoprotein levels. Mipomersen is approved for the treatment of homozygous FH. In this review, we discuss its mechanism, current evidence, limitations of use including adverse events, and impact on health-related quality of life.

Homozygous familiar hypercholesterolemia: still a long way to go

Homozygous familiar hypercholesterolemia (HoFH) is a rare condition characterised by very high levels of low-density lipoprotein cholesterol from birth and an extremely high risk of premature atherosclerotic cardiovascular disease (ACVD).1 Two pathogenic allelic variants at the LDLR, APOB, PCSK9, or LDLRAP1 gene loci are responsible for the disease.2 HoFH is a natural model showing the causal association between LDL cholesterol and ACVD, with cases of coronary disease described in childhood.3 Despite advances in the diagnosis and treatment of hypercholesterolemia in recent years, HoFH continues to be a disease with a low recognition rate in most countries, poor prognosis, low quality of life and life expectancy, and a high cost for health systems.

Dietary tryptophan and the risk of obesity and type 2 diabetes: Total effect and mediation effect of sleep duration.

The aims of this study were to examine the effects of tryptophan consumption on obesity and type 2 diabetes (T2D) risk and whether sleep duration mediates these effects. Overall, data of 7,908 participants were obtained from the China Health and Nutrition Survey (1997-2011). A total of 6,373 and 4,398 participants who reported sleep duration and had blood samples, respectively, were incorporated into subgroup analyses. Multivariate Cox regression models were used to assess the associations between tertiles of tryptophan intake with obesity and T2D. General linear regression models were used to evaluate the effect of tryptophan on sleep time and plasma biomarkers. Dietary tryptophan was significantly associated with decreased risk of obesity and T2D risk (hazard ratio tertile 3 to tertile 1 : 0.602 [95% CI: 0.500-0.724]; 0.693 [95% CI: 0.565-0.850]). Sleep duration was significantly higher, and hemoglobin A1c, total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B-100 (APO-B) were lower in the high tertile of tryptophan compared with the low tertile (p < 0.05). In addition, mediation effects on the associations of tryptophan intake with obesity and T2D risk were observed for sleep duration (estimated mediation percentage: 31.902% and 37.391%). Dietary tryptophan showed advantageous effects on obesity and T2D risk. Furthermore, sleep duration potentially mediated for these effects.

Exploiting Glutamine Consumption in Atherosclerotic Lesions by Positron Emission Tomography Tracer (2S,4R)-4-18F-Fluoroglutamine.

Increased glutamine metabolism by macrophages is associated with development of atherosclerotic lesions. Positron emission tomography/computed tomography (PET/CT) with a glutamine analog (2S,4R)-4-18F-fluoroglutamine (18F-FGln) allows quantification of glutamine consumption in vivo. Here, we investigated uptake of 18F-FGln by atherosclerotic lesions in mice and compared the results with those obtained using the glucose analog 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG). Uptake of 18F-FGln and 18F-FDG by healthy control mice (C57BL/6JRj) and atherosclerotic low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR−/−ApoB100/100) was investigated. The mice were injected intravenously with 18F-FGln or 18F-FDG for in vivo PET/CT imaging. After sacrifice at 70 minutes post-injection, tracer uptake was analyzed by gamma counting of excised tissues and by autoradiography of aorta cryosections, together with histological and immunohistochemical analyses. We found that myocardial uptake of 18F-FGln was low. PET/CT detected lesions in the aortic arch, with a target-to-background ratio (SUVmax, aortic arch/SUVmean, blood) of 1.95 ± 0.42 (mean ± standard deviation). Gamma counting revealed that aortic uptake of 18F-FGln by LDLR−/−ApoB100/100 mice (standardized uptake value [SUV], 0.35 ± 0.06) was significantly higher than that by healthy controls (0.20 ± 0.08, P = 0.03). More detailed analysis by autoradiography revealed that the plaque-to-healthy vessel wall ratio of 18F-FGln (2.90 ± 0.42) was significantly higher than that of 18F-FDG (1.93 ± 0.22, P = 0.004). Immunohistochemical staining confirmed that 18F-FGln uptake in plaques co-localized with glutamine transporter SLC7A7-positive macrophages. Collectively these data show that the 18F-FGln PET tracer detects inflamed atherosclerotic lesions. Thus, exploiting glutamine consumption using 18F-FGln PET may have translational relevance for studying atherosclerotic inflammation.

Association of Lipoproteins with Neutrophil Extracellular Traps in Patients with Abdominal Aortic Aneurysm.

Neutrophil extracellular traps (NETs) are DNA–protein structures released by neutrophils in response to various stimuli, including oxidized, low-density lipoprotein (oxLDL). Accumulating evidence suggests a role for NETs in the pathogenesis of abdominal aortic aneurysm (AAA). In this study, we investigated the potential association of lipoprotein particles and NETs in AAA in comparison to non-AAA control groups. The concentrations of neutrophil myeloperoxidase (MPO), the NET parameters citrullinated histone H3 (citH3) and circulating cell-free DNA (cfDNA), as well as of blood lipids were determined in plasma or serum of patients with AAA (n = 40), peripheral artery occlusive disease (PAD; n = 40) and healthy donors (n = 29). A sandwich ELISA detecting oxidized phosphatidylcholine in association with apolipoprotein B-100 (oxPL/apoB) was applied to measure oxidized phospholipids in circulation. The effect of lipoparticles on NET formation was tested using a DNA release assay with isolated human neutrophils. Plasma MPO, citH3 and cfDNA levels were significantly increased in AAA patients in comparison to healthy donors and PAD patients. Plasma concentrations of citH3 positively correlated with serum oxPL/apoB in AAA patients. In functional in vitro assays, the addition of oxLDL induced NET formation in pre-stimulated neutrophils. In conclusion, our data suggest a promoting role of oxLDL on NET formation in AAA patients.

Glycated apolipoprotein B decreases after bariatric surgery in people with and without diabetes: A potential contribution to reduction in cardiovascular risk

Background and aimsThe causal relationship between LDL cholesterol (LDL-C) and the pathogenesis of atherosclerosis is well established. Previous studies have shown that modifications, glycation and oxidation of LDL enhance its atherogenic potential. Glycation of LDL occurs in it is main protein component, apolipoprotein B100 (ApoB). Our aim was to assess the effect of bariatric surgery on circulating glycApoB levels and understand the factors influencing changes in its circulating levels. MethodsWe measured glycApoB in 49 individuals before, 6 and 12 months after bariatric surgery. We also assessed clinical parameters, lipoproteins, markers of inflammation and glycaemia. Correlation analysis was done to understand associations between changes in variables from baseline to 12 months after surgery. ResultsReductions in glycApoB post-bariatric surgery were significant regardless of whether the patients suffered from type 2 diabetes (T2DM) or took lipid-lowering therapy. There were no significant differences in glycApoB levels at baseline and follow-up between participants with T2DM and those without. GlycApoB declined from baseline in non-diabetics at 6 months and significantly at 12 months (1.09 mg/l vs 0.63 mg/l vs 0.49 mg/l, p < 0.05), and in those with T2DM at 6 months and significantly at 12 months (1.77 mg/l vs 1.03 mg/l vs 0.68 mg/l, p < 0.05). The percentage change in glycApoB correlated (p < 0.05) with changes in glucose (ρ = 0.40), insulin (ρ = 0.41) and HOMA-IR (%) (ρ = 0.43). There were no significant associations between changes in glycApoB and changes in total serum ApoB, LDL-C, high sensitivity C-reactive protein, weight, or BMI. ConclusionsBariatric surgery reduces levels of glycApoB; this reduction is associated with decreased insulin resistance postoperatively. This potentially reflects the potent influence of obesity-related insulin resistance on lipoprotein glycation.Our observations are of potential importance in explaining the effectiveness of bariatric surgery in decreasing cardiovascular disease (CVD) risk in both T2DM and obese individuals without T2DM, as glycation of ApoB is known to be associated with increased atherogenesis.