Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans

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 angiopoie...

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Bibliographic Details
Published in:The Journal of clinical investigation Vol. 119; no. 1; pp. 70 - 79
Main Authors: Romeo, Stefano, Yin, Wu, Kozlitina, Julia, Pennacchio, Len A., Boerwinkle, Eric, Hobbs, Helen H., Cohen, Jonathan C.
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.01.2009
Subjects:
Alleles
Amino Acid Sequence
Angiopoietin-like Proteins
Angiopoietins - genetics
Angiopoietins - metabolism
Animals
Atherosclerosis
Biomedical research
Body fat
Cell Line
Cholesterol
Ethnic Groups - genetics
Fatty acids
Gene mutations
Genetic Variation
Health aspects
Heart
High density lipoprotein
Humans
Hypotheses
Lipid metabolism
Liver
Low density lipoprotein
Metabolism
Mice
Musculoskeletal system
Mutation
Oxidation
Physiological aspects
Physiology
Plasma
Protein Isoforms - genetics
Protein Isoforms - metabolism
Proteins
Tissue Distribution
Triglycerides
Triglycerides - blood
United States
ISSN:0021-9738, 1558-8238
Online Access:Get full text
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Summary: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.
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USDOE Office of Science (SC), Biological and Environmental Research (BER)
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI37118