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Atypical Angiopoietin-Like Protein That Regulates ANGPTL3

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Atypical Angiopoietin-Like Protein That Regulates ANGPTL3 Atypical angiopoietin-like protein that regulates ANGPTL3 Fabiana Quagliarinia,b,1, Yan Wanga,b,c,1, Julia Kozlitinaa,b, Nick V. Grishinc,d,e, Rhonda Hydea,b, Eric Boerwinklef, David M. Valenzuelag, Andrew J. Murphyg, Jonathan C. Cohena,b,2, and Helen H. Hobbsa,b,c,2 aDepartment of Internal Medicine, bDepartment of Molecular Genetics, dDepartment of Biophysics, and eDepartment of Biochemistry, cHoward Hughes Medical Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; fDivision of Epidemiology School of Public Health, University of Texas, Houston, TX 77030; and gRegeneron Pharmaceuticals, Tarrytown, NY 10591 Contributed by Helen H. Hobbs, October 9, 2012 (sent for review August 27, 2012) Angiopoietin-like proteins (ANGPTLs) play major roles in the The role of ANGPTL3 is less well understood. ANGPTL3 is trafficking and metabolism of lipids. Inactivation of ANGPTL3, expressed almost exclusively in the liver (5, 6), and is only −/− a gene located in an intron of DOCK7, results in very low levels modestly regulated by food intake (12). Angptl3 mice have of LDL-cholesterol (C), HDL-C and triglyceride (TAG). We identified increased LPL activity (8, 13, 14), and recombinant ANGPTL3 another ANGPTL family member, ANGPTL8, which is located in the inhibits LPL in vitro (6, 13, 15, 16), leading several investigators corresponding intron of DOCK6. A variant in this family member to propose that ANGPTL3 raises plasma TAG levels by inhib- (rs2278426, R59W) was associated with lower plasma LDL-C and iting LPL activity (13, 14). However, the concentrations of HDL-C levels in three populations. ANGPTL8 is expressed in liver ANGPTL3 used in these studies were supraphysiological. Moreover in some (14, 17), although not all (8) studies, the in- and adipose tissue, and circulates in plasma of humans. Expres- −/− sion of ANGPTL8 was reduced by fasting and increased by refeed- crease in LPL activity in Angptl3 mice has been modest. ing in both mice and humans. To examine the functional relationship ANGPTL3 also inhibits the activity of endothelial lipase (18, 19), which catalyzes the hydrolysis of phospholipids in circulating between the two ANGPTL family members, we expressed ANGPTL3 − − lipoproteins. Angptl3 / mice have a ∼50% reduction in HDL at physiological levels alone or together with ANGPTL8 in livers of levels and a ∼50% increase in heparin-releasable phospholipase mice. Plasma TAG level did not change in mice expressing ANGPTL3 activity (19). Thus, ANGPTL3 may raise HDL levels by inhib- alone, whereas coexpression with ANGPTL8 resulted in hypertrigly- iting endothelial lipase. MEDICAL SCIENCES ceridemia, despite a reduction in circulating ANGPTL3. ANGPTL8 ANGPTL3 is activated by cleavage at a proprotein convertase coimmunoprecipitated with the N-terminal domain of ANGPTL3 in consensus site (221RAPR224) to release the N-terminal domain plasma of these mice. In cultured hepatocytes, ANGPTL8 expression (20). Cleavage is essential for ANGPTL3-mediated inhibition of increased the appearance of N-terminal ANGPTL3 in the medium, lipases; disruption of the consensus site markedly reduces the suggesting ANGPTL8 may activate ANGPTL3. Consistent with this − − effect of the recombinant protein on plasma TAG levels (20). scenario, expression of ANGPTL8 in Angptl3 / mice failed to pro- Here we show that ANGPTL3 is activated by ANGPTL8, mote hypertriglyceridemia. Thus, ANGPTL8, a paralog of ANGPTL3 a paralog of ANGPTL3 that is highly regulated by fasting and that arose through duplication of an ancestral DOCK gene, regulates refeeding in mice and humans. We provide biochemical evidence postprandial TAG and fatty acid metabolism by controlling activa- that ANGPTL8 binds to ANGPTL3 and promotes the appear- tion of its progenitor, and perhaps other ANGPTLs. Inhibition of ance of the cleaved form, and genetic evidence in mice that the ANGPTL8 provides a new therapeutic strategy for reducing plasma two proteins are mechanistically interdependent. We also show lipoprotein levels. that genetic variation in ANGPTL8 is associated with reductions in HDL-C and LDL-C in three populations, thus confirming he angiopoietin-like (ANGPTL) genes encode a family of a role for ANGPTL8 in lipoprotein metabolism in humans. Tsecreted proteins with pleiotropic effects on vascular cells Results (1), lipid metabolism (2), and stem cell biology (3). The family members share a common architecture, comprising an extended Degenerate ANGPTL Family Member Evolutionarily Related to ANGPTL3. N-terminal domain and a C-terminal fibrinogen-like domain. A database search for proteins related to the ANGPTL family Genetic studies have revealed that two closely related family identified ANGPTL8, formerly known as TD26, hepatocellular members, ANGPTL3 and ANGPTL4, play pivotal roles in the carcinoma-associated gene, C19orf80, refeeding-induced fat and trafficking and metabolism of lipids and lipoproteins (4–7). liver (21), and Lipasin (22). ANGPTL8 shares ∼20% identity Mutations that disrupt ANGPTL3 are associated with greatly with the N-terminal domains of ANGPTL3 and ANGPTL4. The reduced plasma levels of triacylglycerol (TAG) and cholesterol protein terminates at residue 198 and therefore lacks a C-ter- in mice (5) and in humans (4). Mice lacking ANGPTL4 also have minal fibrinogen-related domain (Fig. 1A). Sequencing of polyA markedly reduced levels of plasma TAG and cholesterol (8, 9), RNA from both human and mouse liver revealed only a single and sequence variations in ANGPTL4 are associated with lower species of ANGPTL8 transcript. ANGPTL8 and ANGPTL3 are plasma TAG levels in humans (7). located in corresponding introns of DOCK6 and DOCK7, re- TAG synthesized in the gut and liver are incorporated into spectively (Fig. 1B), a configuration that was already established chylomicrons and very low density lipoproteins (VLDL), re- spectively, and delivered to peripheral tissues where they interact with lipoprotein lipase (LPL). LPL hydrolyzes the TAGs, re- Author contributions: F.Q., Y.W., J.C.C., and H.H.H. designed research; F.Q., Y.W., N.V.G., leasing fatty acids to the adjacent tissues. Other intravascular R.H., and E.B. performed research; N.V.G., D.M.V., and A.J.M. contributed new reagents/ lipases, including hepatic lipase and endothelial lipase, further analytic tools; F.Q., Y.W., J.K., R.H., E.B., J.C.C., and H.H.H. analyzed data; and F.Q., Y.W., remodel lipoprotein particles. Several lines of evidence suggest R.H., J.C.C., and H.H.H. wrote the paper. that ANGPTL3 and ANGPTL4 contribute to the partitioning of The authors declare no conflict of interest. TAGs among tissues (2). During fasting, ANGPTL4 levels in- Freely available online through the PNAS open access option. crease in adipose tissue (10) where it inhibits LPL, thus pre- 1F.Q. and Y.W. contributed equally to this work. venting fatty acid uptake from circulating lipoproteins (2, 11). 2To whom correspondence may be addressed. E-mail: Jonathan.Cohen@utsouthwestern. After a meal, expression of ANGPTL4 is markedly reduced, edu or [email protected]. relieving the inhibition of intravascular lipolysis and promoting This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. uptake of dietary lipids into adipose tissue. 1073/pnas.1217552109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1217552109 PNAS Early Edition | 1of6 Downloaded by guest on October 3, 2021 A 125 185 406 we screened public SNP repositories for nonsynonymous variants ANGPTL4 SS Fibrinogen-related in ANGPTL8. A nucleotide transition (c.194C > T, rs2278426) 16 245 460 fi ANGPTL3 SS Fibrinogen-related domain was identi ed that substitutes tryptophan for arginine at residue 21 198 59 (Fig. 1C). In the Dallas Heart Study (DHS), a multiethnic, ANGPTL8 SS Protease Site population-based study of Dallas County (24), the 59W variant was more common among Hispanics [minor allele frequency 50 kb (MAF) = 26%] and African Americans (MAF = 18%) than B DOCK7: chr 1 = 3’ 5’ among European-Americans (MAF 5%) (Table S1). The 59W fi ANGPTL3 variant was signi cantly associated with lower plasma levels of 3’5’ LDL-cholesterol (C) and HDL-C in African Americans and Exon:1 234567500 bp Hispanics. Among African Americans, the largest group in the DHS, plasma levels of LDL-C were 15% lower in WW homo- 20 kb DOCK6: chr 19 zygotes than in RR homozygotes. Heterozygotes had interme- 3’ 5’ diate LDL-C levels. The association was not apparent in European- ANGPTL8 5’ 3’ Americans, presumably because the 59W variant is much less common in this population. The R59W variant was not associated 100 bp with plasma levels of TAG (P = 0.23) (Fig. S2A), or with body mass Exon: 1 2 34 index (BMI), fasting glucose or homeostatic model assessment- C insulin resistance in any ethnic group (Table S1). We replicated the association between the 59W variant and plasma HDL-C and LDL-C levels in African American partic- ipants in the Atherosclerosis Risk in Communities Study (ARIC), a large, prospective, biracial study of heart disease (25) and in the Dallas Biobank, a convenience sample of 4,500 unrelated African Americans from Dallas County (Fig. S2B). Among European- Americans in ARIC, the 59W variant was associated with sig- nificantly lower plasma levels of HDL-C (0.006) (Fig. 2C), but not LDL-C (Table S2). The variant was not associated with Fig. 1. Domain structure and sequence similarity of ANGPTL3, ANGPTL4, plasma TAG levels in ARIC or in the Dallas Biobank (Fig. S2, and ANGPTL8. (A) Domain organization of ANGPTL4, ANGPTL3, and and Tables S2 and S3). In a genome-wide association study that ANGPTL8. (B) Chromosomal location and exon-intron structure of ANGPTL3 predominantly included individuals of European ancestry (26), and ANGPTL8.(C) Multiple sequence alignment of a conserved N-terminal imputed R59W genotypes were associated with both HDL-C (P = − motif in three ANGPTLs. A conserved acidic residue at amino acid 40 in 3.87 × 10 7) and LDL-C (P = 0.006) at the nominal signifi- ANGPTL4 is indicated by an asterisk.
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