Mechanistic journeys into lipid metabolism

Het algemene doel van dit proefschrift betreft de functionele karakterisatie van nieuwe spelers (GPR146) dan wel het ontrafelen van nieuwe rollen van oude spelers (LRP1, ANGPTL3) die betrokken zijn bij dyslipidemie, een gestoorde glucosehuishouding (GALNT2) en/of atherosclerose (LPL, APOA5, LCAT). Er is in dit kader met name aandacht besteed aan moleculaire mechanismes die relevant zijn voor humane ziekebeelden. Hiertoe zijn verschillende benaderingen gebruikt waaronder het uitvoeren van onderzoek in prospectieve humane cohort studies, cellulaire en ook diermodellen

A 3-SNP gene risk score and a metabolic risk score both predict hypertriglyceridemia and cardiovascular disease risk.

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK-Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans

Camtrap DP: an open standard for the FAIR exchange and archiving of camera trap data

Camera trapping has revolutionized wildlife ecology and conservation by providing automated data acquisition, leading to the accumulation of massive amounts of camera trap data worldwide. Although management and processing of camera trap-derived Big Data are becoming increasingly solvable with the help of scalable cyber-infrastructures, harmonization and exchange of the data remain limited, hindering its full potential. There is currently no widely accepted standard for exchanging camera trap data. The only existing proposal, “Camera Trap Metadata Standard” (CTMS), has several technical shortcomings and limited adoption. We present a new data exchange format, the Camera Trap Data Package (Camtrap DP), designed to allow users to easily exchange, harmonize and archive camera trap data at local to global scales. Camtrap DP structures camera trap data in a simple yet flexible data model consisting of three tables (Deployments, Media and Observations) that supports a wide range of camera deployment designs, classification techniques (e.g., human and AI, media-based and event-based) and analytical use cases, from compiling species occurrence data through distribution, occupancy and activity modeling to density estimation. The format further achieves interoperability by building upon existing standards, Frictionless Data Package in particular, which is supported by a suite of open software tools to read and validate data. Camtrap DP is the consensus of a long, in-depth, consultation and outreach process with standard and software developers, the main existing camera trap data management platforms, major players in the field of camera trapping and the Global Biodiversity Information Facility (GBIF). Under the umbrella of the Biodiversity Information Standards (TDWG), Camtrap DP has been developed openly, collaboratively and with version control from the start. We encourage camera trapping users and developers to join the discussion and contribute to the further development and adoption of this standard. Biodiversity data, camera traps, data exchange, data sharing, information standardspublishedVersio

Novel regulators of plasma lipid levels

Purpose of review To highlight very recent studies identifying novel regulatory molecules and mechanisms in plasma lipid metabolism. Recent findings Two novel regulatory mechanisms of LDL receptor (LDLR) intracellular trafficking have been described. The "COMMD/CCDC22/CCDC93'' and "Wiskott-Aldrich syndrome protein and SCAR homologue'' complexes were found to be involved in LDLR endosomal sorting and recycling, whereas the GRP94 was shown to protect LDLR from early degradation within the hepatocyte secretory pathway. Additionally, the transcription factors PHD1 and Bmal1 were identified to regulate LDL-C levels in mice by modulating cholesterol excretion. Important advances are reported on the relevance of two Genome Wide Association Studies hits: Reassessment of GALNT2 showed, in contrast to previous reports, that loss of GALNT2 reduces HDL-cholesterol in humans and other mammalian species, while phospholipid transfer protein was identified as an additional target of GALNT2. Tetratricopeptide repeat domain protein 39B was found to promote ubiquitination and degradation of Liver X receptor, and its deficiency increased HDL-cholesterol and cholesterol removal while also inhibiting lipogenesis in mice. Summary The unraveling of mechanisms how new factors modulate plasma lipid levels keep providing interesting opportunities to rationally design novel therapies to treat cardiovascular disease but also metabolic disorders

Mendelian Disorders of High-Density Lipoprotein Metabolism

High-density lipoproteins (HDLs) are a highly heterogeneous and dynamic group of the smallest and densest lipoproteins present in the circulation. This review provides the current molecular insight into HDL metabolism led by articles describing mutations in genes that have a large affect on HDL cholesterol levels through their roles in HDL and triglyceride metabolism. Using this information from both human and animal studies, it is discussed how HDL is produced, remodeled in the circulation, affected by factors that control the metabolism of triglyceride-rich lipoproteins, how it helps maintain cellular cholesterol homeostasis, and, finally, how it is catabolized. It can be concluded that HDL cholesterol as a trait is genetically heterogeneous, with as many as 40 genes involved. In most cases, only heterozygotes of gene variants are known, and HDL cholesterol as a trait is inherited in an autosomal-dominant manner. Only 3 Mendelian disorders of HDL metabolism are currently known, which are inherited in an autosomal-recessive mode

ANGPTL8 has both endocrine and autocrine effects on substrate utilization

The angiopoietin-like protein ANGPTL8 (A8) is one of 3 ANGPTLs (A8, A3, A4) that coordinate changes in triglyceride (TG) delivery to tissues by inhibiting lipoprotein lipase (LPL), an enzyme that hydrolyzes TG. Previously we showed that A8, which is expressed in liver and adipose tissue, is required to redirect dietary TG from oxidative to storage tissues following food intake. Here we show that A8 from liver and adipose tissue have different roles in this process. Mice lacking hepatic A8 have no circulating A8, high intravascular LPL activity, low plasma TG levels, and evidence of decreased delivery of dietary lipids to adipose tissue. In contrast, mice lacking A8 in adipose tissue have higher postprandial TG levels and similar intravascular LPL activity and plasma A8 levels and higher levels of plasma TG. Expression of A8, together with A4, in cultured cells reduced A4 secretion and A4-mediated LPL inhibition. Thus, hepatic A8 (with A3) acts in an endocrine fashion to inhibit intravascular LPL in oxidative tissues, whereas A8 in adipose tissue enhances LPL activity by autocrine/paracrine inhibition of A4. These combined actions of A8 ensure that TG stores are rapidly replenished and sufficient energy is available until the next meal

A 3-SNP gene risk score and a metabolic risk score both predict hypertriglyceridemia and cardiovascular disease risk.

BACKGROUND: Evidence on the causal link between plasma triglyceride (TG) levels and risk for cardiovascular disease (CVD) has recently emerged. Individuals with the metabolic syndrome have an increased risk for acquiring elevated TG levels later in life. Moreover, common DNA sequence variations in genes affecting TG levels identify individuals at risk for elevated plasma TG levels. OBJECTIVE: We evaluated whether a 3-single nucleotide polymorphism (SNP) TG gene risk score (GRS) and a metabolic risk score (MetRS) both improved CVD risk prediction. METHODS: A 3-SNP GRS and MetRS were generated in the EPIC-Norfolk cohort (n = 20,074) based on 3 SNPs in LPL and APOA5 or the number of Metabolic Syndrome criteria present (maximum 5), respectively. The associations between the 3-SNP GRS, MetRS, TG levels, and CVD risk were evaluated. RESULTS: The 3-SNP GRS and MetRS were both linearly associated with plasma TG levels, that is, +0.25 mmol/L [95% CI 0.22-0.27] per allele change (P < .001) and +0.72 mmol/L [95% CI 0.70-0.73] per increase of number of metabolic syndrome risk score points (P < .001), respectively. We observed a positive association between the 3-SNP GRS and the risk of CVD with an adjusted hazard ratio (HR) of 1.35 [95% CI 1.04-1.74] for the highest versus the lowest GRS, which was independent of the MetRS. For the MetRS, the adjusted HR was 2.03 [95% CI 1.73-2.40] for the highest versus the lowest MetRS. CONCLUSION: Both the 3-SNP GRS and the MetRS are associated with increased plasma TG levels and increased risk for CVD

Complete and Partial Lecithin:Cholesterol Acyltransferase Deficiency Is Differentially Associated With Atherosclerosis

BACKGROUND: Lecithin:cholesterol acyltransferase (LCAT) is the sole enzyme that esterifies cholesterol in plasma. Its role in the supposed protection from atherogenesis remains unclear because mutations in LCAT causing fish-eye disease (FED) or familial LCAT deficiency (FLD) have been reported to be associated with more or instead less carotid atherosclerosis, respectively. This discrepancy may be associated with the loss of cholesterol esterification on only apolipoprotein AI (FED) or on both apolipoprotein AI- and apolipoprotein B-containing lipoproteins (FLD), an aspect that has thus far not been investigated