Alternative titles; symbols
HGNC Approved Gene Symbol: ANGPTL4
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:8,364,155-8,374,370 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | Plasma triglyceride level QTL, low | 615881 | Autosomal dominant | 3 |
Using a subtractive cloning strategy to identify downstream targets of peroxisome proliferator-activated receptor-gamma (PPARG; 601487), and by screening cDNA libraries, Yoon et al. (2000) isolated mouse and human cDNAs encoding PGAR. The 406-amino acid, 60-kD human PGAR protein, which shares 75% amino acid identity with the mouse protein, is a member of the angiopoietin family of secreted proteins and bears highest similarity to angiopoietin-2 (ANGPT2; 601922). Like other members of this family, PGAR contains a predicted coiled-coil quaternary structure, and the authors hypothesized that PGAR may form multimeric or other higher-order structures. PGAR has a secretory signal peptide, 3 potential N-glycosylation sites, and 4 cysteines that may be available for intramolecular disulfide bonding. Northern blot analysis detected a 2-kb PGAR transcript that was highly enriched in white fat and placenta. In situ hybridization analysis revealed expression of mouse Pgar at low levels in most organs and connective tissue at embryonic day 13.5 (E13.5). Between E15.5 and E18.5, strongest expression of Pgar was in brown fat. Northern blot analysis detected elevated levels of Pgar expression in mouse models of obesity and diabetes. Alterations in nutrition and leptin (164160) administration in mice modulated Pgar expression in vivo.
Kersten et al. (2000) identified mouse Pgar, which they called Fiaf (fasting-induced adipose factor), using a subtractive hybridization assay to identify PPARA (170998) target genes. Northern blot analysis detected expression of Fiaf in mouse white and brown adipose tissue, with weak expression in lung, kidney, and liver.
Romeo et al. (2009) examined levels of ANGPTL4 mRNA in 48 human tissues and found the highest expression in the liver, with the next highest level in the pericardium. The level of ANGPTL4 transcript in adipose tissue was only 10% of that found in liver; low levels of ANGPTL4 were also present in the adrenal glands, lung, pancreas, and placenta, with only trace amounts detected in other tissues.
Perdiguero et al. (2011) showed that Angptl4 was expressed in mouse retinal endothelial cells in a developmentally regulated manner.
By radiation hybrid analysis, Yoon et al. (2000) mapped the PGAR gene to chromosome 19p13.3.
Yoon et al. (2000) demonstrated that PPARG ligand-induced transcription of PGAR follows a rapid time course typical of immediate-early genes and occurs in the absence of protein synthesis. Using a culture model system, they observed that induction of the PGAR transcript coincides with hormone-dependent adipocyte differentiation. Yoon et al. (2000) concluded that PGAR is a bona fide target of PPARG and may have a role in regulation of systemic lipid metabolism or glucose homeostasis.
Using a combination of wildtype, Ppara mutant, and Pparg mutant mice, Kersten et al. (2000) demonstrated that Fiaf mRNA expression is stimulated by PPARA in liver and by PPARG in white adipose tissue. Expression of Fiaf was upregulated in liver and white adipose tissue during fasting. Western blot analysis showed that the abundance of Fiaf in plasma decreased with high-fat feeding, an effect directly opposite that observed with leptin.
Lipoprotein lipase (LPL; 609708) has a central role in lipoprotein metabolism, and ANGPTL4 inhibits LPL activity, retarding lipoprotein catabolism. Sukonina et al. (2006) found that the N-terminal coiled-coil domain of murine Angptl4 bound transiently to Lpl and the interaction converted Lpl from a catalytically active dimer to an inactive monomer. In rat adipose tissue, Angptl4 mRNA turned over rapidly, and changes in Angptl4 mRNA abundance correlated inversely with Lpl activity, both during the fed-to-fasted and fasted-to-fed transitions. Sukonina et al. (2006) concluded that ANGPTL4 is a fasting-induced controller of LPL in adipose tissue, acting extracellularly as an unfolding molecular chaperone.
Romeo et al. (2009) found that conditioned medium from cells expressing wildtype ANGPTL4 consistently suppressed LPL activity by more than 90%. Conversely, when conditioned medium containing equivalent quantities of mutant ANGPTL4 proteins (e.g., E40K, 605910.0001) was added to the lipase assay, no suppression of LPL activity was observed. Furthermore, the mutant ANGPTL4 proteins failed to suppress LPL even when added at concentrations 10-fold higher than those at which the wildtype protein completely inhibited the enzyme. The inhibitory effects of ANGPTL4 were specific for the salt-sensitive component of postheparin plasma lipase activity.
Yin et al. (2009) examined the steps involved in the synthesis and posttranslational processing of ANGPTL4, and the effects of the E40K mutation. Expression of the wildtype and mutant proteins in HEK293A cells indicated that ANGPTL4 formed dimers and tetramers in cells prior to secretion and cleavage of the protein. After cleavage at a canonical proprotein convertase cleavage site (p.161_164RRKR), the oligomeric structure of the N-terminal domain was retained, whereas the C-terminal fibrinogen-like domain dissociated into monomers. Inhibition of cleavage did not interfere with oligomerization of ANGPTL4 or with its ability to inhibit lipoprotein lipase, whereas mutations that prevented oligomerization severely compromised the capacity of the protein to inhibit LPL. ANGPTL4 containing the E40K substitution was synthesized and processed normally, but no monomers or oligomers of the N-terminal fragments accumulated in the medium; medium from these cells failed to inhibit LPL activity. Parallel experiments performed in mice recapitulated these results. Yin et al. (2009) concluded that oligomerization, but not cleavage, of ANGPTL4 is required for LPL inhibition, and that the E40K substitution destabilizes the protein after secretion, preventing the extracellular accumulation of oligomers and abolishing the ability of the protein to inhibit LPL activity.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that mark and mediate breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Two that were not functionally validated but that achieved the highest statistical significance (p less than 0.000001) were FSCN1 (602689) and ANGPTL4. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Galaup et al. (2006) found that expression of human ANGPTL4 in mice by DNA electrotransfer prevented metastasis of mouse lung carcinoma cells by inhibiting tumor cell intravasation from the primary tumor to the lymphatic or blood vessels without affecting angiogenesis or lymphangiogenesis. Expression of ANGPTL4 also inhibited extravasation of mouse melanoma cells from the circulation to lungs, as well as histamine-induced vascular permeability. In vitro, transfected mouse melanoma cells expressing and secreting human ANGPTL4 showed reduced migration, invasion, adhesion, and cytoskeleton organization compared with control cells. Galaup et al. (2006) concluded that ANGPTL4 prevents the metastatic process by inhibiting vascular activity and tumor cell motility and invasiveness.
Using clinical, functional, and molecular evidence, Padua et al. (2008) found that TGF-beta (see TGFB1, 190180) activity in primary breast tumors was associated with development of lung metastasis but not bone metastasis. ANGPTL4 was a critical TGF-beta target gene in this process, and induction of ANGPTL4 primed tumor cells for disruption of lung capillary endothelial junctions to selectively seed lung metastasis.
Zheng et al. (2012) showed that the human immune inhibitory receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; 604815) and its mouse ortholog paired immunoglobulin-like receptor (PIRB) are receptors for several angiopoietin-like proteins, including ANGPTL4. LILRB2 and PIRB are expressed on human and mouse hematopoietic stem cells, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of hematopoietic stem cells. In mouse transplantation acute myeloid leukemia models, a deficiency in intracellular signaling of PIRB resulted in increased differentiation of leukemia cells, revealing that PIRB supports leukemia development. Zheng et al. (2012) concluded that their study indicated an unexpected functional significance of classical immune inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.
Gur-Cohen et al. (2019) identified lymphatic capillaries as critical stem cell-niche components. In skin, lymphatics form intimate networks around hair follicle stem cells. When hair follicles regenerate, lymphatic-stem cell connections become dynamic. Using a mouse model, Gur-Cohen et al. (2019) identified a secretome switch in stem cells that controls lymphatic behavior. Resting stem cells express Angptl7 (618517), promoting lymphatic drainage. Activated stem cells switch to Angptl4, triggering transient lymphatic dissociation and reduced drainage. When lymphatics are perturbed or the secretome switch is disrupted, hair follicles cycle precociously and tissue regeneration becomes asynchronous.
Adipocytes secrete a variety of proteins that regulate glucose and lipid metabolism. As a first step toward elucidating the role of adipokines in lipid metabolism in humans, Romeo et al. (2007) examined the effect of sequence variation in ANGPTL4, a gene whose expression is induced in adipose tissue and liver during fasting. They sequenced the 7 exons and the intron-exon boundaries of the ANGPTL4 gene in 3,551 participants in the Dallas Heart Study. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant, E40K (605910.0001), present in approximately 3% of European Americans, was associated with significantly lower plasma levels of triglyceride (TGQTL; 615881) and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans, suggesting population-specific relaxation of purifying selection.
Romeo et al. (2009) resequenced the coding regions of the genes encoding ANGPTL3 (604774), ANGPTL4, ANGPTL5 (607666), and ANGPTL6 (609336) and identified multiple rare nonsynonymous sequence variations that were associated with low plasma triglyceride levels but not with other metabolic phenotypes. Functional studies revealed that all mutant alleles of ANGPTL3 and ANGPTL4 that were associated with low plasma triglyceride levels interfered either with the synthesis or secretion of the protein or with the ability of the ANGPTL to inhibit LPL. A total of 1% of the Dallas Heart Study population and 4% of those participants with a plasma triglyceride 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 triglyceride metabolism, and multiple alleles at these loci cumulatively contribute to variability in plasma triglyceride levels in humans. Romeo et al. (2009) also found that the mutations in ANGPTL4 that interfered with their ability to inhibit LPL activity were in the N-terminal region of the protein, consistent with the observation that the N-terminal portion of ANGPTL4 interacts with the enzyme. Of the 31 variants in the low-triglyceride group, 8 (26%) introduced a premature termination codon or altered a consensus splice site; 13 interfered with secretion of the protein from cells; and 6 resulted in proteins that were secreted but failed to inhibit LPL activity. Romeo et al. (2009) reported 11 variants in ANGPTL4 that are associated with low plasma triglyceride levels in the lowest quartile. Four were associated with no expression; these were nonsense and splice site mutations. Five were associated with absent secretion of the protein, and 2 of these failed to inhibit LPL.
The gut microbial community (microbiota) is dominated by anaerobic bacteria, and includes approximately 500-1,000 species whose collective genomes are estimated to contain 100 times more genes than our own human genome. The microbiota can be viewed as a metabolic 'organ' exquisitely tuned to our physiology to perform functions that we have not had to evolve on our own. These functions include the ability to process otherwise indigestible components of our diet, such as plant polysaccharides. Backhed et al. (2004) used normal and genetically engineered gnotobiotic (germ-free) mice to address the hypothesis that the microbiota acts through an integrated host signaling pathway to regulate energy storage in the host. They produced 'conventionalization' of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals. They observed a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promoted absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, was selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal, and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1 (179615) -/- animals indicated that these host responses do not require mature lymphocytes. The findings suggested that the microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host.
Perdiguero et al. (2011) found that Angptl4 deletion in mice resulted in some lethality during development. The small number of Angptl4 -/- survivors were viable and fertile with no obvious defects. However, sprouting, branching, and maturation of blood vessels were affected during developmental angiogenesis of Angptl4 -/- retina. The vascular network of Angptl4 -/- retina displayed a delay in maturation during postnatal development, which was characterized by alterations in endothelial cell junctions and defects in pericyte coverage, as well as increased vessel permeability. In addition, hypoxia-driven pathologic neovascularization was compromised in Angptl4 -/- retina.
In a population-based resequencing of the adipokine gene ANGPTL4, Romeo et al. (2007) found association between lower plasma triglyceride levels and higher high density lipoprotein (HDL) and a glu40-to-lys (E40K) variant that was found in approximately 3% of European Americans. The authors concluded that sequence variation in ANGPTL4 primarily affects plasma levels of triglycerides (TGQTL; 615881) but also affects other related metabolic parameters, including high density lipoprotein cholesterol, low density lipoprotein cholesterol, and possibly fasting insulin levels.
Talmud et al. (2008) found that the E40K mutation, with a minor allelic frequency of 2%, was associated with significantly low triglyceride levels (-20.4%, p = less than 0.0001) in a study of 2,772 men. However, Talmud et al. (2008) found that the mutation, despite being associated with lower triglyceride levels, actually conferred a higher odds ratio for coronary heart disease risk (1.48, with a range of 1.11-1.96, p = 0.007), independent of triglycerides.
Yin et al. (2009) found that ANGPTL4 containing the E40K substitution was synthesized and processed normally, but no monomers or oligomers of the N-terminal fragments accumulated in the medium; medium from these cells failed to inhibit LPL activity.
Dewey et al. (2016) sequenced the exons of ANGPTL4 in DNA samples from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. Triglyceride levels were 13% lower and HDL cholesterol levels were 7% higher among carriers of the E40K variant than noncarriers. Carriers of E40K were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; p = 0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes.
In a resequencing analysis of patients from the Dallas Heart Study, Romeo et al. (2009) identified a lys217-to-ter (K217X) nonsense mutation in individuals with plasma triglyceride levels in the lowest quartile (TGQTL; 615881). The mutation was associated with absent expression of the protein. The mutation was not found in the Exome Variant Server database (Hamosh, 2014). Scott (2014) stated that the mutation occurs in isoform 1 of ANGPTL4.
Backhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., Semenkovich, C. F., Gordon, J. I. The gut microbiota as an environmental factor that regulates fat storage. Proc. Nat. Acad. Sci. 101: 15718-15723, 2004. [PubMed: 15505215] [Full Text: https://doi.org/10.1073/pnas.0407076101]
Dewey, F. E., Gusarova, V., O'Dushlaine, C., Gottesman, O., Trejos, J., Hunt, C., Van Hout, C. V., Habegger, L., Buckler, D., Lai, K.-M. V., Leader, J. B., Murray, M. F., and 14 others. Inactivating variants in ANGPTL4 and risk of coronary artery disease. New Eng. J. Med. 374: 1123-1133, 2016. [PubMed: 26933753] [Full Text: https://doi.org/10.1056/NEJMoa1510926]
Galaup, A., Cazes, A., Le Jan, S., Philippe, J., Connault, E., Le Coz, E., Mekid, H., Mir, L. M., Opolon, P., Corvol, P., Monnot, C., Germain, S. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. Proc. Nat. Acad. Sci. 103: 18721-18726, 2006. [PubMed: 17130448] [Full Text: https://doi.org/10.1073/pnas.0609025103]
Gur-Cohen, S., Yang, H., Baksh, S. C., Miao, Y., Levorse, J., Kataru, R. P., Liu, X., de la Cruz-Racelis, J., Mehrara, B. J., Fuchs, E. Stem cell-driven lymphatic remodeling coordinates tissue regeneration. Science 366: 1218-1225, 2019. [PubMed: 31672914] [Full Text: https://doi.org/10.1126/science.aay4509]
Hamosh, A. Personal Communication. Baltimore, Md. 7/10/2014.
Kersten, S., Mandard, S., Tan, N. S., Escher, P., Metzger, D., Chambon, P., Gonzalez, F. J., Desvergne, B., Wahli, W. Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J. Biol. Chem. 275: 28488-28493, 2000. [PubMed: 10862772] [Full Text: https://doi.org/10.1074/jbc.M004029200]
Minn, A. J., Gupta, G. P., Siegel, P. M., Bos, P. D., Shu, W., Giri, D. D., Viale, A., Olshen, A. B., Gerald, W. L., Massague, J. Genes that mediate breast cancer metastasis to lung. Nature 436: 518-524, 2005. [PubMed: 16049480] [Full Text: https://doi.org/10.1038/nature03799]
Padua, D., Zhang, X. H.-F., Wang, Q., Nadal, C., Gerald, W. L., Gomis, R. R., Massague, J. TGF-beta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133: 66-77, 2008. [PubMed: 18394990] [Full Text: https://doi.org/10.1016/j.cell.2008.01.046]
Perdiguero, E. G., Galaup, A., Durand, M., Teillon, J., Philippe, J., Valenzuela, D. M., Murphy, A. J., Yancopoulos, G. D., Thurston, G., Germain, S. Alteration of developmental and pathological retinal angiogenesis in angptl4-deficient mice. J. Biol. Chem. 286: 36841-36851, 2011. [PubMed: 21832056] [Full Text: https://doi.org/10.1074/jbc.M111.220061]
Romeo, S., Pennacchio, L. A., Fu, Y., Boerwinkle, E., Tybjaerg-Hansen, A., Hobbs, H. H., Cohen, J. C. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nature Genet. 39: 513-516, 2007. [PubMed: 17322881] [Full Text: https://doi.org/10.1038/ng1984]
Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119: 70-79, 2009. [PubMed: 19075393] [Full Text: https://doi.org/10.1172/JCI37118]
Scott, A. F. Personal Communication. Baltimore, Md 7/14/2014.
Sukonina, V., Lookene, A., Olivecrona, T., Olivecrona, G. Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc. Nat. Acad. Sci. 103: 17450-17455, 2006. [PubMed: 17088546] [Full Text: https://doi.org/10.1073/pnas.0604026103]
Talmud, P. J., Smart, M., Presswood, E., Cooper, J. A., Nicaud, V., Drenos, F., Palmen, J., Marmot, M. G., Boekholdt, S. M., Wareham, N. J., Khaw, K.-T., Kumari, M., Humphries, S. E. ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk. Arterioscler. Thromb. Vasc. Biol. 28: 2319-2325, 2008. [PubMed: 18974381] [Full Text: https://doi.org/10.1161/ATVBAHA.108.176917]
Yin, W., Romeo, S., Chang, S., Grishin, N. V., Hobbs, H. H., Cohen, J. C. Genetic variation in ANGPTL4 provides insights into protein processing and function. J. Biol. Chem. 284: 13213-13222, 2009. [PubMed: 19270337] [Full Text: https://doi.org/10.1074/jbc.M900553200]
Yoon, J. C., Chickering, T. W., Rosen, E. D., Dussault, B., Qin, Y., Soukas, A., Friedman, J. M., Holmes, W. E., Spiegelman, B. M. Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation. Molec. Cell. Biol. 20: 5343-5349, 2000. [PubMed: 10866690] [Full Text: https://doi.org/10.1128/MCB.20.14.5343-5349.2000]
Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Canto, A. P., Chen, S.-H., Wang, H.-Y., Ward, E. S., Zhang, C. C. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485: 656-660, 2012. Note: Erratum: Nature 488: 684 only, 2012. [PubMed: 22660330] [Full Text: https://doi.org/10.1038/nature11095]