Abstract
The relative activity of lipoprotein lipase (LPL) in different tissues controls the
partitioning of lipoprotein-derived fatty acids between sites of fat storage (adipose
tissue) and oxidation (heart and skeletal muscle). Here we used a reverse genetic
strategy to test the hypothesis that 4 angiopoietin-like proteins (ANGPTL3, -4, -5,
and -6) play key roles in triglyceride (TG) metabolism in humans. We re-sequenced the
coding regions of the genes encoding these proteins and identified multiple rare
nonsynonymous (NS) sequence variations that were associated with low plasma TG levels
but not with other metabolic phenotypes. Functional studies revealed that all mutant
alleles of ANGPTL3 and ANGPTL4 that were associated
with low plasma TG levels interfered either with the synthesis or secretion of the
protein or with the ability of the ANGPTL protein to inhibit LPL. A total of 1% of
the Dallas Heart Study population and 4% of those participants with a plasma TG in
the lowest quartile had a rare loss-of-function mutation in ANGPTL3,
ANGPTL4, or ANGPTL5. Thus, ANGPTL3, ANGPTL4, and
ANGPTL5, but not ANGPTL6, play nonredundant roles in TG metabolism, and multiple
alleles at these loci cumulatively contribute to variability in plasma TG levels in
humans.
Authors
Stefano Romeo, Wu Yin, Julia Kozlitina, Len A. Pennacchio, Eric Boerwinkle, Helen H. Hobbs, Jonathan C. Cohen
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