Three members of the angiopoietin-like (ANGPTL) family of proteins, ANGPTL3, ANGPTL4 and ANGPTL8, are known regulators of plasma triacylglycerol levels. Recently, these three proteins have garnered considerable interest as potential targets for therapeutically reducing plasma triacylglycerol levels and improving cardiovascular outcomes. In this issue of Diabetologia, Janssen et al (https://doi.org/10.1007/s00125-018-4583-5) and Vatner et al (https://doi.org/10.1007/s00125-018-4579-1) show that reducing levels of ANGPTL4 and ANGPTL8, respectively, could have the added benefit of improving glucose tolerance. Interestingly, the improvements in glucose tolerance observed in both studies, both done in rodents, were coupled with increased fat mass. These findings suggest that funnelling lipids to adipose tissue and away from ectopic sites could be beneficial and strengthen the argument for pursuing the therapeutic targeting of ANGPTL proteins.
Diabetes Gut microbiota Insulin sensitivity Lipolysis Lipoprotein lipase Lipoproteins
This is a preview of subscription content, log in to check access.
The author was the sole contributor to this paper.
Funding for the Davies’ lab work on angiopoietin-like proteins is supported by grants from the National Institutes of Health (R01HL130146 and R01HL134787). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
Duality of interest
The author declares that there is no duality of interest associated with this manuscript.
Köster A, Chao YB, Mosior M et al (2005) Transgenic angiopoietin-like (Angptl)4 overexpression and targeted disruption of Angptl4 and Angptl3: regulation of triglyceride metabolism. Endocrinology 146:4943–4950CrossRefPubMedGoogle Scholar
Zhang R (2012) Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun 424:786–792CrossRefPubMedGoogle Scholar
Romeo S, Yin W, Kozlitina J et al (2009) Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest 119:70–79PubMedGoogle Scholar
Romeo S, Pennacchio LA, Fu Y et al (2007) Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 39:513–516CrossRefPubMedPubMedCentralGoogle Scholar
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators, Stitziel NO, Stirrups KE et al (2016) Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 374:1134–1144CrossRefPubMedCentralGoogle Scholar
Peloso GM, Auer PL, Bis JC et al (2014) Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet 94:223–232CrossRefPubMedPubMedCentralGoogle Scholar
Yoshida K, Shimizugawa T, Ono M, Furukawa H (2002) Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res 43:1770–1772CrossRefPubMedGoogle Scholar
Sukonina V, Lookene A, Olivecrona T, Olivecrona G (2006) Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue. Proc Natl Acad Sci U S A 103:17450–17455CrossRefPubMedPubMedCentralGoogle Scholar
Haller JF, Mintah IJ, Shihanian LM et al (2017) ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. J Lipid Res 58:1166–1173CrossRefPubMedGoogle Scholar
Shimamura M, Matsuda M, Yasumo H et al (2007) Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol 27:366–372CrossRefPubMedGoogle Scholar
Mattijssen F, Alex S, Swarts HJ et al (2014) Angptl4 serves as an endogenous inhibitor of intestinal lipid digestion. Mol Metab 3:135–144CrossRefPubMedGoogle Scholar
Graham MJ, Lee RG, Brandt TA et al (2017) Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 377:222–232CrossRefPubMedGoogle Scholar
Fu Z, Abou-Samra AB, Zhang R (2015) A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase. Sci Rep 5:18502CrossRefPubMedPubMedCentralGoogle Scholar
Gusarova V, Banfi S, Alexa-Braun CA et al (2017) ANGPTL8 blockade with a monoclonal antibody promotes triglyceride clearance, energy expenditure, and weight loss in mice. Endocrinology 158:1252–1259CrossRefPubMedPubMedCentralGoogle Scholar
Desai U, Lee E-C, Chung K et al (2007) Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc Natl Acad Sci U S A 104:11766–11771CrossRefPubMedPubMedCentralGoogle Scholar
Lichtenstein L, Mattijssen F, de Wit NJ et al (2010) Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab 12:580–592CrossRefPubMedPubMedCentralGoogle Scholar
Robciuc MR, Maranghi M, Lahikainen A et al (2013) Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol 33:1706–1713CrossRefPubMedGoogle Scholar
Xu A, Lam MC, Chan KW et al (2005) Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci U S A 102:6086–6091CrossRefPubMedPubMedCentralGoogle Scholar
Mandard S, Zandbergen F, van Straten E et al (2006) The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem 281:934–944CrossRefPubMedGoogle Scholar
Janssen AWF, Katiraei S, Bartosinska B et al (2018) Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota. Diabetologia https://doi.org/10.1007/s00125-018-4583-5
Wang Y, Quagliarini F, Gusarova V et al (2013) Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci 110:16109–16114CrossRefPubMedPubMedCentralGoogle Scholar
Vatner DF, Goedeke L, Camporez J-PG et al (2018) Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia https://doi.org/10.1007/s00125-018-4579-1
Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI (2007) Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci 104:979–984CrossRefPubMedPubMedCentralGoogle Scholar