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Objective— Loss-of-function (LOF) variants in theANGPTL3 (angiopoietin-like protein 3) 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 Results— We studied individuals carrying S17X LOF mutation inANGPTL3 (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 LOF carriers and noncarriers in fasting state and after a high-fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in LDL (low-density lipoprotein) cholesterol (0.74 SD units lower concentration per LOF allele [95% CI, 0.42–1.06]) as observed for many TRL (triglyceride-rich lipoprotein) measures, including VLDL (very-low-density lipoprotein) cholesterol (0.75 [95% CI, 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 TRLs and their remnants. Further, β-hydroxybutyrate was elevated (0.55 [95% CI, 0.21–0.89]). HomozygousANGPTL3 LOF carriers showed essentially no postprandial increase in TRLs and fatty acids, without evidence for adverse compensatory metabolic effects.Conclusions— In addition to overall triglyceride- and LDL cholesterol–lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within TRLs and their remnants. Further,ANGPTL3 LOF carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid β-oxidation. The detailed metabolic profile in human knockouts ofANGPTL3 reinforces inactivation ofANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.

Metabolomic Signature of Angiopoietin-Like Protein 3 Deficiency in Fasting and Postprandial State