Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study

Cardiovascular Diabetology

Kyung Mook Choi²  Seon Mi Kim¹  Dong Seop Choi²  Sei Hyun Baik²  Nan Hee Kim²  Sin Gon Kim²  Ji-A Seo²  Hye Jin Yoo²  Hyun Jung Lee²  Soon Young Hwang³  Min Jung Lee²  Hye Soo Chung² 

[1] Department of Family Medicine, College of Medicine, Korea University, Seoul, Korea;Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea;Department of Biostatistics, College of Medicine, Korea University, Seoul, Korea

关键词: Triglycerides;    LDL;    HDL;    Dyslipidemias;    Cholesterol;    ANGPTL8;    ANGPTL3;   

Others  :  1235272
DOI  :  10.1186/s12933-015-0324-y

 received in 2015-09-17, accepted in 2015-12-28,  发布年份 2016

【 摘 要 】

Background

Previous studies have shown that angiopoietin-like protein 8 (ANGPTL8), also called as betatrophin, acts together with ANGPTL3 to regulate lipid metabolism, glucose metabolism, and energy homeostasis. Moreover, ANGPTL8 promotes proliferation of pancreatic β-cells and induces insulin secretion. However, there are no previous longitudinal studies in humans.

Methods

We analyzed the age- and sex-matched data of 240 normal weight and overweight Korean children from the Korean Metabolic disorders and Obesity Study in Elementary School children (K-MOSES), a prospective observational cohort study.

Results

At baseline, ANGPTL8 concentrations were positively associated with triglycerides (TG) (r = 0.168, P = 0.010), whereas ANGPTL3 levels were associated with fasting insulin (r = 0.248, P < 0.001) and the homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.197, P = 0.002). Although both ANGPTL8 and ANGPTL3 levels did not differ between children with normal weight and children with overweight, ANGPTL8 levels were increased in males compared to females (341.2 [267.4–436.5] vs. 270.2 [213.9–378.8] pg/ml, P = 0.001). In particular, there was no significant inter-relationship between circulating ANGPTL8 and ANGPTL3 concentrations in Korean boys and girls (r = −0.073, P = 0.265). Multivariate analysis showed that baseline ANGPTL8 concentrations were independently associated with future changes of serum TG levels in Korean children after adjusting for confounding factors after a 3 year follow-up period (r = −0.165, P = 0.016).

Conclusions

This longitudinal study demonstrated for the first time that baseline ANGPTL8 levels were associated with baseline and future changes in TG levels in Korean children.

【 授权许可】

   
2016 Chung et al.

【 图 表 】

Fig.1.

【 参考文献 】

• [1]Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell. 2013; 153:747-758.
• [2]Zhu JZ, Yu CH, Li YM. Betatrophin provides a new insight into diabetes treatment and lipid metabolism (review). Biomed Rep. 2014; 2:447-451.
• [3]Zhang R. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels. Biochem Biophys Res Commun. 2012; 424:786-792.
• [4]Ren G, Kim JY, Smas CM. Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism. Am J Physiol Endocrinol Metab. 2012; 303:E334-E351.
• [5]Espes D, Lau J, Carlsson PO. Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes. Diabetologia. 2014; 57:50-53.
• [6]Hu H, Sun W, Yu S, Hong X, Qian W, Tang B, Wang D, Yang L, Wang J, Mao C et al.. Increased circulating levels of betatrophin in newly diagnosed type 2 diabetic patients. Diabetes Care. 2014; 37:2718-2722.
• [7]Gusarova V, Alexa CA, Na E, Stevis PE, Xin Y, Bonner-Weir S, Cohen JC, Hobbs HH, Murphy AJ, Yancopoulos GD, Gromada J. ANGPTL8/betatrophin does not control pancreatic beta cell expansion. Cell. 2014; 159:691-696.
• [8]Santulli G. Angiopoietin-like proteins: a comprehensive look. Front Endocrinol (Lausanne). 2014; 5:4.
• [9]Quagliarini F, Wang Y, Kozlitina J, Grishin NV, Hyde R, Boerwinkle E, Valenzuela DM, Murphy AJ, Cohen JC, Hobbs HH. Atypical angiopoietin-like protein that regulates ANGPTL3. Proc Natl Acad Sci USA. 2012; 109:19751-19756.
• [10]Zhang R, Abou-Samra AB. A dual role of lipasin (betatrophin) in lipid metabolism and glucose homeostasis: consensus and controversy. Cardiovasc Diabetol. 2014; 13:133. BioMed Central Full Text
• [11]Choi KM, Yannakoulia M, Park MS, Cho GJ, Kim JH, Lee SH, Hwang TG, Yang SJ, Kim TN, Yoo HJ et al.. Serum adipocyte fatty acid-binding protein, retinol-binding protein 4, and adiponectin concentrations in relation to the development of the metabolic syndrome in Korean boys: a 3 year prospective cohort study. Am J Clin Nutr. 2011; 93:19-26.
• [12]Lee SH, Kim SM, Park HS, Choi KM, Cho GJ, Ko BJ, Kim JH. Serum 25-hydroxyvitamin D levels, obesity and the metabolic syndrome among Korean children. Nutr Metab Cardiovasc Dis. 2013; 23:785-791.
• [13]Korean physical growth standards for children and adolescents. Korean Pediatric Society, Seoul; 2007.
• [14]Taylor SJ, Whincup PH, Hindmarsh PC, Lampe F, Odoki K, Cook DG. Performance of a new pubertal self-assessment questionnaire: a preliminary study. Paediatr Perinat Epidemiol. 2001; 15:88-94.
• [15]Mattijssen F, Kersten S. Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 2012; 1821:782-789.
• [16]Jung CH, Lee WJ, Lee MJ, Kang YM, Jang JE, Leem J, La Lee Y, Seol SM, Yoon HK, Park JY. Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes. Cardiovasc Diabetol. 2015; 14:35. BioMed Central Full Text
• [17]Nidhina Haridas PA, Soronen J, Sadevirta S, Mysore R, Quagliarini F, Pasternack A, Metso J, Perttila J, Leivonen M, Smas CM et al.. Regulation of angiopoietin-like proteins (ANGPTLs) 3 and 8 by insulin. J Clin Endocrinol Metab. 2015; 100:E1299-E1307.
• [18]Chen X, Lu P, He W, Zhang J, Liu L, Yang Y, Liu Z, Xie J, Shao S, Du T et al.. Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance. J Clin Endocrinol Metab. 2015; 100:E96-E100.
• [19]Ebert T, Kralisch S, Hoffmann A, Bachmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M, Tonjes A, Fasshauer M. Circulating angiopoietin-like protein 8 is independently associated with fasting plasma glucose and type 2 diabetes mellitus. J Clin Endocrinol Metab. 2014; 99:E2510-E2517.
• [20]Abu-Farha M, Abubaker J, Noronha F, Al-Khairi I, Cherian P, Alarouj M, Bennakhi A, Elkum N. Lack of associations between betatrophin/ANGPTL8 level and C-peptide in type 2 diabetic subjects. Cardiovasc Diabetol. 2015; 14:112. BioMed Central Full Text
• [21]Gao T, Jin K, Chen P, Jin H, Yang L, Xie X, Yang M, Hu C, Yu X. Circulating betatrophin correlates with triglycerides and postprandial glucose among different glucose tolerance statuses—a case-control study. PLoS One. 2015; 10:e0133640.
• [22]Gokulakrishnan K, Manokaran K, Pandey GK, Amutha A, Ranjani H, Anjana RM, Mohan V. Relationship of betatrophin with youth onset type 2 diabetes among Asian Indians. Diabetes Res Clin Pract. 2015; 109:71-76.
• [23]Gomez-Ambrosi J, Pascual E, Catalan V, Rodriguez A, Ramirez B, Silva C, Gil MJ, Salvador J, Fruhbeck G. Circulating betatrophin concentrations are decreased in human obesity and type 2 diabetes. J Clin Endocrinol Metab. 2014; 99:E2004-E2009.
• [24]Fenzl A, Itariu BK, Kosi L, Fritzer-Szekeres M, Kautzky-Willer A, Stulnig TM, Kiefer FW. Circulating betatrophin correlates with atherogenic lipid profiles but not with glucose and insulin levels in insulin-resistant individuals. Diabetologia. 2014; 57:1204-1208.
• [25]Wang Y, Quagliarini F, Gusarova V, Gromada J, Valenzuela DM, Cohen JC, Hobbs HH. Mice lacking ANGPTL8 (betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis. Proc Natl Acad Sci USA. 2013; 110:16109-16114.
• [26]Koishi R, Ando Y, Ono M, Shimamura M, Yasumo H, Fujiwara T, Horikoshi H, Furukawa H. Angptl3 regulates lipid metabolism in mice. Nat Genet. 2002; 30:151-157.
• [27]Shimizugawa T, Ono M, Shimamura M, Yoshida K, Ando Y, Koishi R, Ueda K, Inaba T, Minekura H, Kohama T, Furukawa H. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem. 2002; 277:33742-33748.
• [28]Shimamura M, Matsuda M, Kobayashi S, Ando Y, Ono M, Koishi R, Furukawa H, Makishima M, Shimomura I. Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes. Biochem Biophys Res Commun. 2003; 301:604-609.
• [29]Shimamura M, Matsuda M, Yasumo H, Okazaki M, Fujimoto K, Kono K, Shimizugawa T, Ando Y, Koishi R, Kohama T et al.. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler Thromb Vasc Biol. 2007; 27:366-372.
• [30]Robciuc MR, Maranghi M, Lahikainen A, Rader D, Bensadoun A, Oorni K, Metso J, Minicocci I, Ciociola E, Ceci F et al.. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol. 2013; 33:1706-1713.
• [31]Yilmaz Y, Ulukaya E, Atug O, Dolar E. Serum concentrations of human angiopoietin-like protein 3 in patients with nonalcoholic fatty liver disease: association with insulin resistance. Eur J Gastroenterol Hepatol. 2009; 21:1247-1251.
• [32]Mehta N, Qamar A, Qu L, Qasim AN, Mehta NN, Reilly MP, Rader DJ. Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. Arterioscler Thromb Vasc Biol. 2014; 34:1057-1063.
• [33]Angelakopoulou A, Shah T, Sofat R, Shah S, Berry DJ, Cooper J, Palmen J, Tzoulaki I, Wong A, Jefferis BJ et al.. Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: cardiovascular biomarker genetics collaboration. Eur Heart J. 2012; 33:393-407.
• [34]Wang Y, McNutt MC, Banfi S, Levin MG, Holland WL, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl Acad Sci USA. 2015; 112:11630-11635.