Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

Minicocci, Ilenia; Tikka, Anna; Poggiogalle, Eleonora; Metso, Jari; Mestice, Anna; Ceci, Fabrizio; Labbadia, Giancarlo; Fontana, Mario; Costanzo, Alessia Di; Maranghi, Marianna; Rosano, Aldo; Ehnholm, Christian; Donini, Lorenzo Maria; Jauhiainen, Matti; Arca, Marcello

doi:10.1194/jlr.p066183

Cited by 50 publications

(55 citation statements)

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“…Because most people are in a non-fasting state for the majority of the day, studying the effects on postprandial metabolism may further contribute to explain the cardioprotective mechanism of ANGPTL3 deficiency. We have previously reported highly reduced postprandial response in triglycerides among ANGPTL3 LOF homozygotes 21 . Here we further examined the detailed metabolic effects of ANGPTL3 deficiency after a high fat meal.…”

Section: Introductionmentioning

confidence: 85%

“…Plasma levels of ANGPTL3 protein were undetectable in homozygotes, while heterozygotes had 51% lower concentration compared to that of noncarriers. The three genotype classes were comparable for dietary intake, physical activity, smoking prevalence and use of anti-inflammatory medications 21 . Descriptive statistics for all metabolic biomarkers tested are reported in Supplementary Table 1.…”

Section: Study Participantsmentioning

confidence: 97%

“…An overview of the study design in shown in the "Graphic summary". The study population and the design of the oral fat tolerance challenge have been described in detail elsewhere 21 . Briefly, 6 homozygous and 32 heterozygous carriers of ANGPTL3 S17X LOF mutation (henceforth ANGPTL3 LOF) and 38 non-carriers were considered in the present study.…”

Section: Study Cohort Of Angptl3 Loss-of-function Carriersmentioning

confidence: 99%

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Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state

Tikkanen

Minicocci

Hällfors

et al. 2018

Preprint

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Objective Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically-induced ANGPTL3 deficiency in fasting and postprandial state. Approach and ResultsWe studied individuals carrying S17X loss-of-function mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between loss-of-function carriers and noncarriers in fasting state and after a high fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in low-density lipoprotein cholesterol (0.74 SD-units lower concentration per loss-of-function allele [95%CI 0.42-1.06]) as observed for many triglyceride-rich lipoprotein measures, including very-low-density lipoprotein cholesterol (0.75 [0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within triglyceride-rich lipoproteins and their remnants. Further, beta-hydroxybutyrate was elevated (0.55 [0.21-0.89]). Homozygous ANGPTL3 loss-of-function carriers showed essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids, without evidence for adverse compensatory metabolic effects. ConclusionsIn addition to overall triglyceride and low-density lipoprotein cholesterol lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within triglyceride-rich lipoproteins and their remnants. Further, ANGPTL3 loss-of-function carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid beta-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.

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Section: Introductionmentioning

confidence: 85%

Section: Study Participantsmentioning

confidence: 97%

Section: Study Cohort Of Angptl3 Loss-of-function Carriersmentioning

confidence: 99%

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Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state

Tikkanen

Minicocci

Hällfors

et al. 2018

Preprint

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“…Studies in both mice and humans have demonstrated ANGPTL3 to be a potent inhibitor of LPL, particularly in the post-prandial state (41). Consistent with effects of rare mutations in 3 additional endogenous regulators of LPL, APOA5 (10), APOC3 (11,37), and ANGPTL4 (16,36), loss of ANGPTL3 function appears to result in gain of LPL activity, reduced triglyceride-rich lipoproteins, and protection from coronary disease.…”

Section: Discussionmentioning

confidence: 99%

ANGPTL3 Deficiency and Protection Against Coronary Artery Disease

Stitziel¹,

Khera²,

Wang

et al. 2017

Journal of the American College of Cardiology

378

282

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BACKGROUND Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES The study goal was to leverage 3 distinct lines of evidence – a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in myocardial infarction (MI) patients – to test if ANGPTL3 deficiency is associated with lower risk for CAD. METHODS We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 individuals with CAD and 158,200 controls. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 individuals presenting with MI and 3,232 controls. RESULTS The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 individuals was a heterozygous carrier for an LOF mutation. Compared to those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS ANGPTL3 deficiency is associated with protection from CAD.

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“…Suppression of AGPTL3 is one of the mechanisms by which thyroxine reduces LDL-C. Patients with AGPTL3 deficiency have elevated LPL activity and low LDL-C levels as well as highly reduced triglycerides, VLDL and HDL-C levels [60]. Thus, it is considered a potential target to further control cholesterol and apoB levels.…”

Section: Aso Therapy To Angiopoetin-like Protein-3 (Angptl3)mentioning

confidence: 99%