Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice

Xu, Aimin; Lam, Michael C.; Chan, Kok Weng; Wang, Yu; Zhang, Jialiang; Hoo, Ruby L. C.; Xu, Jian Yu; Chen, Baoying; Chow, Wing-Sun; Tso, Annette W. K.; Lam, Karen S. L.

doi:10.1073/pnas.0408452102

Cited by 269

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Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice

Xu, Aimin, Lam, Michael C., Chan, Kok Weng, Wang, Yu, Zhang, Jialiang, Hoo, Ruby L. C., Xu, Jian Yu, Chen, Baoying, Chow, Wing-Sun, Tso, Annette W. K., Lam, Karen S. L.·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0408452102

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Abstract

Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db/db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.

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Angptl4 prevents LPL dimerization and thereby prevents LPL activation.
“Angptl4 is primarily expressed in adipose tissue and liver, induced by fasting and secreted into the circulation [4], where it prevents LPL dimerization and thereby preventing LPL activation [5–8].”
From Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity (2015) · cites this paper as [7]

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Leptin and the regulation of body weight in mammals
Friedman, J. M., & Halaas, J. L. (1998) · Nature · doi:10.1038/27376 · Cited by 5,405
Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., et al. (2002) · Nature Medicine · doi:10.1038/nm788 · Cited by 4,238
The adipocyte-secreted protein Acrp30 enhances hepatic insulin action
Berg, A. H., Combs, T. P., Du, X., Brownlee, M., & Scherer, P. E. (2001) · Nature Medicine · doi:10.1038/90992 · Cited by 2,526
The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice
Xu, A., Wang, Y., Keshaw, H., Xu, L. Y., Lam, K. S. L., & Cooper, G. J. S. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200317797 · Cited by 1,298
Self-citation
Minireview: Adiposity, Inflammation, and Atherogenesis
Lyon, C. J., Law, R. E., & Hsueh, W. A. (2003) · Endocrinology · doi:10.1210/en.2003-0285 · Cited by 761
PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3
Koo, S.-H., Satoh, H., Herzig, S., Lee, C.-H., Hedrick, S., Kulkarni, R., Evans, R. M., Olefsky, J., & Montminy, M. (2004) · Nature Medicine · doi:10.1038/nm1044 · Cited by 550
Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity
Stiles, B., Wang, Y., Stahl, A., Bassilian, S., Lee, W. P., Kim, Y.-J., Sherwin, R., Devaskar, S., Lesche, R., Magnuson, M. A., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308617100 · Cited by 436
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Research works printed but not linked: 21

10.1210/jc.2004-0395 · DOI · Paper page
10.1161/01.ATV.0000099786.99623.EF · DOI
10.1128/MCB.20.14.5343-5349.2000 · DOI · Paper page
10.1074/jbc.M004029200 · DOI · Paper page
10.1042/bj3460603 · DOI
10.1074/jbc.M403058200 · DOI · Paper page
10.1194/jlr.C200010-JLR200 · DOI · Paper page
10.1194/jlr.M400138-JLR200 · DOI · Paper page
10.1038/sj.ijo.0801834 · DOI
10.1074/jbc.M208756200 · DOI
10.1210/en.2003-1140 · DOI
Keppler, D. & Decker, K. (1974) in Methods of Enzymatic Analysis, ed. Bergmeyer, N. U. (VCH, Weinheim, Germany), Vol. 6, pp. 2225-2228.
10.1074/jbc.M200601200 · DOI
10.1074/jbc.274.10.6718 · DOI
10.1210/endo.137.10.8828476 · DOI · Paper page
10.1210/en.2003-0288 · DOI
10.1016/S0140-6736(00)90002-3 · DOI
10.2337/diabetes.52.12.2905 · DOI
10.1074/jbc.M307583200 · DOI · Paper page
10.1073/pnas.98.4.2005 · DOI
10.1074/jbc.M309469200 · DOI

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Authors: Xu, A., Lam, M. C., Chan, K. W., Wang, Y., Zhang, J., Hoo, R. L. C., Xu, J. Y., Chen, B., Chow, W.-S., Tso, A. W. K., & Lam, K. S. L.
Affiliations: Departments of Medicine and Biochemistry, Research Center of Heart, Brain, Hormone, and Healthy Aging, and Genome Research Center, University of Hong Kong, Hong Kong, China
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2005-04-18
Volume: 102
Issue: 17
Pages: 6086-6091
ISSN: 0027-8424
1091-6490
DOI: 10.1073/pnas.0408452102
Cited by: 269
References: 8
Language: en

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Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice

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