Dyslipidemia in obesity results from excessive production and impaired clearance of triglyceride-rich (TG-rich) lipoproteins, which are particularly pronounced in the postprandial state. Here, we investigated the impact of Roux-en-Y gastric bypass (RYGB) surgery on postprandial VLDL1 and VLDL2 apoB and TG kinetics and their relationship with insulin-responsiveness indices. Morbidly obese patients without diabetes who were scheduled for RYGB surgery (n = 24) underwent a lipoprotein kinetics study during a mixed-meal test and a hyperinsulinemic-euglycemic clamp study before the surgery and 1 year later. A physiologically based computational model was developed to investigate the impact of RYGB surgery and plasma insulin on postprandial VLDL kinetics. After the surgery, VLDL1 apoB and TG production rates were significantly decreased, whereas VLDL2 apoB and TG production rates remained unchanged. The TG catabolic rate was increased in both VLDL1 and VLDL2 fractions, but only the VLDL2 apoB catabolic rate tended to increase. Furthermore, postsurgery VLDL1 apoB and TG production rates, but not those of VLDL2, were positively correlated with insulin resistance. Insulin-mediated stimulation of peripheral lipoprotein lipolysis was also improved after the surgery. In summary, RYGB resulted in reduced hepatic VLDL1 production that correlated with reduced insulin resistance, elevated VLDL2 clearance, and improved insulin sensitivity in lipoprotein lipolysis pathways.

Background Vascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro. Methods C57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions. Results Imatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake. Conclusion Imatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib.

Objective: The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5- 2 H 3 )-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. Conclusions: In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04722068.

During angiogenesis, vascular endothelial growth factor A (VEGFA) regulates endothelial cell (EC) survival, tip cell formation, and stalk cell proliferation via VEGF receptor 2 (VEGFR2). VEGFR2 can interact with VEGFR2 co-receptors such as heparan sulfate proteoglycans (HSPGs) and neuropilin 2 (NRP2), but the exact roles of these co-receptors, or of sulfatase 2 (SULF2), an enzyme that removes sulfate groups from HSPGs and inhibits HSPG-mediated uptake of very low density lipoprotein (VLDL), in angiogenesis and tip cell biology are unknown. In the present study, we investigated whether the modulation of binding of VEGFA to VEGFR2 by knockdown of SULF2 or NRP2 affects sprouting angiogenesis, tip cell formation, proliferation of non-tip cells, and EC survival, or uptake of VLDL. To this end, we employed VEGFA splice variant 121, which lacks an HSPG binding domain, and VEGFA splice variant 165, which does have this domain, in in vitro models of angiogenic tip cells and vascular sprouting. We conclude that VEGFA165 and VEGFA121 have similar inducing effects on tip cells and sprouting in vitro, and that the binding of VEGFA165 to HSPGs in the extracellular matrix does not seem to play a role, as knockdown of SULF2 did not alter these effects. Co-binding of NRP2 appears to regulate VEGFA–VEGFR2-induced sprout initiation, but not tip cell formation. Finally, as the addition of VLDL increased sprout formation but not tip cell formation, and as VLDL uptake was limited to non-tip cells, our findings suggest that VLDL plays a role in sprout formation by providing biomass for stalk cell proliferation.

Introduction The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering. Areas covered The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering. Expert opinion Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-L-Rx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.

Objective:Both glucose and triglyceride production are increased in Type 2 diabetes andnon-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesisto explain these paradoxical observations has been selective hepatic insulinresistance, wherein insulin drives de novo lipogenesis (DNL), whilefailing to suppress glucose production. Here, we aimed to test this hypothesisin humans.ResearchDesign and Methods: We recruited obese subjects who metcriteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed:i) insulin-mediated regulation of hepatic and peripheral glucose metabolismusing hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose,ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), andiii) hepatocellular insulin signaling in liver biopsies collected duringbariatric surgery.Results:As compared with subjects without NAFLD, subjects with NAFLD demonstratedimpaired insulin-mediated suppression of glucose production and attenuated -notincreased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulinlipogenesis was intact. Hepatocellular insulin signaling, assessed for thefirst time in humans, exhibited a proximal block in insulin-resistant subjects:signaling was attenuated from the level of the insulin receptor through bothglucose and lipogenesis pathways. The carbohydrate-regulated lipogenictranscription factor ChREBP was increased in subjects with NAFLD. Conclusions: Acute increases in lipogenesis in humans withNAFLD are not explained by altered molecular regulation of lipogenesis througha paradoxical increase in lipogenic insulin action; rather, increases inlipogenic substrate availability may be the key.

In the article cited above, “Amsterdam University Medical Center, Amsterdam” was mistakenly displayed for affiliations 1 and 2. The institution and city for both should have read “Leiden University Medical Center, Leiden.” The editors apologize for the errors. The online version of the article (https://doi.org/10.2337/db18-1360) has been updated to correct this.

BACKGROUND:Genetic factors partly determine the risk for premature myocardial infarction (MI). OBJECTIVES:We report the identification of a novel rare genetic variant in a kindred with an autosomal dominant trait for premature MI and atherosclerosis and explored the association of a common nonsynonymous variant in the same gene with the risk of ischemic heart disease (IHD) in a population-based study. METHODS:Next-generation sequencing was performed in a small pedigree with premature MI or subclinical atherosclerosis. A common variant, rs8141797 A>G (p.Asn466Ser), in sushi domain-containing protein 2 (SUSD2) was studied in the prospective Copenhagen General Population Studies (N = 105,408) for association with IHD. RESULTS:A novel heterozygous nonsense mutation in SUSD2 (c.G583T; p.Glu195Ter) was associated with the disease phenotype in the pedigree. SUSD2 protein was expressed in aortic specimens in the subendothelial cell layer and around the vasa vasorum. Furthermore, the minor G-allele of rs8141797 was associated with per allele higher levels of SUSD2 mRNA expression in the heart and vasculature. In the Copenhagen General Population Study, hazard ratios for IHD were 0.92 (95% CI: 0.87-0.97) in AG heterozygotes and 0.86 (0.62-1.19) in GG homozygotes vs noncarrriers (P-trend = .002). Finally, in meta-analysis including 73,983 IHD cases and 215,730 controls, the odds ratio for IHD per G-allele vs A-allele was 0.93 (0.90-0.96) (P = 4.6 × 10-7). CONCLUSIONS:The identification of a truncating mutation in SUSD2, which was associated with premature MI and subclinical atherosclerosis, combined with the finding that a common missense variant in SUSD2 was strongly associated with a lower risk of IHD, suggest that SUSD2 may alter the risk of atherosclerosis.

BACKGROUND AND AIMS:The rare ASGR1 del12 variant is associated with a beneficial effect on coronary artery disease (CAD) that is disproportionate to the small reductions in plasma LDL cholesterol (LDLc). This unexplained benefit has sparked the debate on potential additional pleiotropic effects of ASGR1 variants. Since ASGR1 has also been implicated in platelet homeostasis, we evaluated platelet function in heterozygous ASGR1 del12 carriers and controls. In addition, we compared the magnitude of various LDLc lowering genetic scores in the UK-biobank using Mendelian randomization. METHODS:Desialylation of platelet surface glycoproteins and platelet aggregation capacity were measured in 12 carriers and 10 controls. We selected 3 common genetic variants in the ASGR1 locus that were significantly associated with plasma LDLc and assessed the association with coronary artery disease (CAD) and compared it with the effects of HMCGR, LDLR, NCI1L1 and PCSK9 gene scores. RESULTS:Platelet surface GlcNAC residues were significantly lower in carriers but platelet aggregation did not differ. The relative risk reduction of ASGR1 GRS on CAD and myocardial infarction per 10 mg/dl LDLc reduction was 23% (OR 0.77, 95% CI 0.62-0.96). This risk reduction was proportionally similar to the gene risk scores in HMCGR, NPC1L1, PCSK9, and LDLR. CONCLUSIONS:Unlike previous reports, we did not find any evidence for a pleiotropic effect of the rare del12 variant in the ASGR1 locus on CAD, as platelet function did not differ between carriers and controls. Moreover, the observed effect of ASGR1 variants on CAD risk was proportional to the reduction in plasma LDLc levels.

OBJECTIVE:Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.DESIGN:Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.RESULTS:We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.CONCLUSION:Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.TRIAL REGISTRATION NUMBER:NTR4327.

OBJECTIVE:Increasing evidence indicates that intestinal microbiota play a role in diverse metabolic processes via intestinal butyrate production. Human bariatric surgery data suggest that the gut-brain axis is also involved in this process, but the underlying mechanisms remain unknown.METHODS:We compared the effect of fecal microbiota transfer (FMT) from post-Roux-en-Y gastric bypass (RYGB) donors vs oral butyrate supplementation on (123I-FP-CIT-determined) brain dopamine transporter (DAT) and serotonin transporter (SERT) binding as well as stable isotope-determined insulin sensitivity at baseline and after 4 weeks in 24 male and female treatment-naïve metabolic syndrome subjects. Plasma metabolites and fecal microbiota were also determined at these time points.RESULTS:We observed an increase in brain DAT after donor FMT compared to oral butyrate that reduced this binding. However, no effect on body weight and insulin sensitivity was demonstrated after post-RYGB donor feces transfer in humans with metabolic syndrome. Increases in fecal levels of Bacteroides uniformis were significantly associated with an increase in DAT, whereas increases in Prevotella spp. showed an inverse association. Changes in the plasma metabolites glycine, betaine, methionine, and lysine (associated with the S-adenosylmethionine cycle) were also associated with altered striatal DAT expression.CONCLUSIONS:Although more and larger studies are needed, our data suggest a potential gut microbiota-driven modulation of brain dopamine and serotonin transporters in human subjects with obese metabolic syndrome. These data also suggest the presence of a gut-brain axis in humans that can be modulated.NTR REGISTRATION:4488.

In 2019, Atherosclerosis started a two-step review process to further improve the journal's quality. All submissions are seen, judged, and discussed by the editor-in-chief and the co-editors in a weekly telephone conference. As a result, more than 60% of all submissions are rejected upfront. The remaining articles are transferred to the associate editors, who invite expert reviewers. Including revision, these pre-selected submissions have approximately a 50% chance of being accepted. With this revised review process, the acceptance rate of Atherosclerosis has decreased from more than 30% to less than 20%. We put in place these new procedures to ensure that only the best quality papers are published in our journal.

The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the ‘oral sodium butyrate capsules first’ or ‘oral placebo capsules first’ study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. Netherlands Trial Register: NL4832 (www.trialregister.nl). Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

OBJECTIVE:STAP1, encoding for STAP1 (signal transducing adaptor family member 1), has been reported as a candidate gene associated with familial hypercholesterolemia. Unlike established familial hypercholesterolemia genes, expression of STAP1 is absent in liver but mainly observed in immune cells. In this study, we set out to validate STAP1 as a familial hypercholesterolemia gene. Approach and Results: A whole-body Stap1 knockout mouse model (Stap1-/-) was generated and characterized, without showing changes in plasma lipid levels compared with controls. In follow-up studies, bone marrow from Stap1-/- mice was transplanted to Ldlr-/- mice, which did not show significant changes in plasma lipid levels or atherosclerotic lesions. To functionally assess whether STAP1 expression in B cells can affect hepatic function, HepG2 cells were cocultured with peripheral blood mononuclear cells isolated from heterozygotes carriers of STAP1 variants and controls. The peripheral blood mononuclear cells from STAP1 variant carriers and controls showed similar LDLR mRNA and protein levels. Also, LDL (low-density lipoprotein) uptake by HepG2 cells did not differ upon coculturing with peripheral blood mononuclear cells isolated from either STAP1 variant carriers or controls. In addition, plasma lipid profiles of 39 carriers and 71 family controls showed no differences in plasma LDL cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, and lipoprotein(a) levels. Similarly, B-cell populations did not differ in a group of 10 STAP1 variant carriers and 10 age- and sex-matched controls. Furthermore, recent data from the UK Biobank do not show association between STAP1 rare gene variants and LDL cholesterol.CONCLUSIONS:Our combined studies in mouse models and carriers of STAP1 variants indicate that STAP1 is not a familial hypercholesterolemia gene.

Previously, we identified plasma microRNA (miR) profiles that associate with markers of microvascular injury in patients with diabetic nephropathy (DN). However, miRs circulate in extracellular vesicles (EVs) or in association with HDL or the RNA-binding protein argonaute-2 (Ago-2). Given that the EV- and HDL-mediated miR transfer toward endothelial cells (ECs) regulates cellular quiescence and inflammation, we hypothesized that the distribution of miRs among carriers affects microvascular homeostasis in DN. Therefore, we determined the miR expression in EV, HDL, and Ago-2 fractions isolated from EDTA plasma of healthy control subjects, patients with diabetes mellitus (DM) with or without early DN (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2), and patients with DN (eGFR <30 mL/min/1.73 m2). Consistent with our hypothesis, we observed alterations in miR carrier distribution in plasma of patients with DM and DN compared with healthy control subjects. Both miR-21 and miR-126 increased in EVs of patients with DN, whereas miR-660 increased in the Ago-2 fraction and miR-132 decreased in the HDL fraction. Moreover, in vitro, differentially expressed miRs improved EC barrier formation (EV-miR-21) and rescued the angiogenic potential (HDL-miR-132) of ECs cultured in serum from patients with DM and DN. In conclusion, miR measurement in EVs, HDL, and Ago-2 may improve the biomarker sensitivity of these miRs for microvascular injury in DN, while carrier-specific miRs can improve endothelial barrier formation (EV-miR-21/126) or exert a proangiogenic response (HDL-miR-132).

Background. HIV-associated cardiovascular disease (CVD) risk in combination antiretroviral therapy (cART)-treated perinatally HIV-infected patients (PHIV+) remains unknown due to the young age of this population. Lipoprotein(a) (Lp(a)) has been established as an independent causal risk factor for CVD in the general population but has not been well established in the population of PHIV+. Methods. We cross-sectionally compared lipid profiles, including nonfasting Lp(a), together with total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides between 35 cART-treated PHIV+ children aged 8-18 years and 37 controls who were matched for age, sex, ethnicity, and socioeconomic status. We explored associations between Lp(a) and disease- and treatment-related factors (inflammation, monocyte activation, and vascular), biomarkers, and neuroimaging outcomes using linear regression models. Results. PHIV+ children had significantly higher levels of Lp(a) compared with controls (median, 43.6 [21.6-82.4] vs 21.8 [16.8-46.6] mg/dL; P = .033). Other lipid levels were comparable between groups. Additional assessment of apolipoprotein B, apolipoprotein CIII, apolipoprotein E, and APOE genotype revealed no significant differences. Higher Lp(a) levels were associated with higher plasma apoB levels and with lower monocyte chemoattractant protein-1 and TG levels in PHIV+ children. Lp(a) was not associated with HIV- or cART-related variables or with neuroimaging outcomes. Conclusions. cART-treated PHIV+ children appear to have higher levels of Lp(a) compared with ethnicity-matched controls, which may implicate higher CVD risk in this population. Future research should focus on the association between Lp(a) and (sub) clinical CVD measurements in cART-treated PHIV+ patients.

No differences detected in Lp(a) concentration in patients grouped according to their Dutch Lipid Clinic Network (DLCN) Criteria for FH clinical diagnosis, n=140.p=0.285;Test Kruskal-Wallis Lp(a) in patients genotyped for FH (NGS for LDLR, APOB, PCSK9, APOE and LDLRap1),(n=95) No differences were observed between patients with Positive or Negative genetic study.p=0.214;U-Mann WhitneyTest Conclusions: a-In a subgroup of our hypercholesterolemic cohort, we verified an independence between Lp(a) and LDL-C levels.b-Lp(a) did not show associations with FH clinical diagnosis (DLCN) nor with FH genetic testing results.c-However, it must be highlighted that the coexistence of increased LDL-C and Lp(a) levels impair the severity and prognosis of CVD d-Testing for elevated Lp(a) during cascade screening for FH is effective in identifying relatives with high Lp(a) and increased risk ASCVD (SAFEHEART, Mata P et al, 2019, 73,9:1029)

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco-isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1-CDG patients and compared them with 11 age- and gender-matched, healthy controls. B4GALT1-CDG patients have significantly lowered non-high density lipoprotein cholesterol (HDL-c) and total cholesterol to HDL-c ratio compared with controls and larger HDL particles. Plasma CETP was hypoglycosylated and less active in B4GALT1-CDG patients compared to matched controls. Our study provides insight into the role of protein glycosylation in human lipoprotein homeostasis. The hypogalactosylated, hypo-active CETP found in patients with B4GALT1-CDG indicates a role of protein galactosylation in regulating plasma HDL and LDL. Patients with B4GALT1-CDG have large HDL particles probably due to hypogalactosylated, hypo-active CETP.

This series of reviews is centered around the novel developments in gene regulation to better understand the underlying pathobiology of cardiovascular disease. The process of gene regulation in cardiovascular disease is complex and involves many regulatory mechanisms located at different systemic levels. In the traditional approach, a simple transcriptome signature based on gene expression analysis, in combination with a genome analysis including whole exome sequence or genome wide single nucleotide polymorphism (GWAS) analysis, was sufficient to explain basic gene regulation [ [1] Lusis A.J. Mar R. Pajukanta P. Genetics of atherosclerosis. Annu. Rev. Genom. Hum. Genet. 2004; 5: 189-218 Crossref PubMed Scopus (247) Google Scholar ]. However, it is now well established that environmental factors greatly impact the cardiovascular outcome, suggesting the importance of additional pathways so far greatly ignored [ [2] Messner B. Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 509-515 Crossref PubMed Scopus (584) Google Scholar , [3] Mayne S.L. Auchincloss A.H. Michael Y.L. Impact of policy and built environment changes on obesity-related outcomes: a systematic review of naturally occurring experiments. Obes. Rev. 2015; 16: 362-375 Crossref PubMed Scopus (189) Google Scholar ]. New improved technologies, together with more advanced mathematical modelling, allow for a more in depth analysis of detailed regulatory processes, including transcriptional control by histones and non-histone proteins and their impact on cardiovascular disease [ [4] Costantino S. Libby P. Kishore R. Tardif J.C. El-Osta A. Paneni F. Epigenetics and precision medicine in cardiovascular patients: from basic concepts to the clinical arena. Eur. Heart J. 2017; 14: 4150-4158 Google Scholar ]. In the review series published in this issue of Atherosclerosis, we aim to provide an overview of the current knowledge in the field and open novel pathways for target identification of novel therapeutics.

Over the last century, many studies have demonstrated that low-density lipoprotein (LDL) is a key risk factor of cardiovascular diseases (CVD) related to atherosclerosis. Thus, for these CVD patients, LDL lowering agents are commonly used in the clinic to reduce the risk for CVD. LDL, upon modification, will develop distinct inflammatory and proatherogenic potential, leading to impaired endothelial integrity, influx of immune cells and subsequent increased foam cell formation. LDL can also directly affect peripheral monocyte composition, rendering them in a more favorable position to migrate and accumulate in the subendothelial space. It has become apparent that other lipoprotein particles, such as triglyceride- rich lipoproteins or remnants (TRL) and lipoprotein(a) [Lp(a)] may also impact on atherogenic pathways. Evidence is accumulating that Lp(a) can promote peripheral monocyte activation, eventually leading to increased transmigration through the endothelium. Similarly, remnant cholesterol has been identified to play a key role in endothelial dysfunction and monocyte behavior. In this review, we will discuss recent developments in understanding the role of different lipoproteins in the context of inflammation at both the level of the monocyte and the endothelium.