Angptl4 Protects against Severe Proinflammatory Effects of Saturated Fat by Inhibiting Fatty Acid Uptake into Mesenteric Lymph Node Macrophages

L.L. Lichtenstein, F.B.J. Mattijssen, N.J.W. de Wit, A. Georgiadi, G.J.E.J. Hooiveld, R. van der Meer, Y. He, L. Qi, A. Köster, J.T. Tamsma, N.S. Tan, M.R. Müller, A.H. Kersten

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Abstract

Dietary saturated fat is linked to numerous chronic diseases, including cardiovascular disease. Here we study the role of the lipoprotein lipase inhibitor Angptl4 in the response to dietary saturated fat. Strikingly, in mice lacking Angptl4, saturated fat induces a severe and lethal phenotype characterized by fibrinopurulent peritonitis, ascites, intestinal fibrosis, and cachexia. These abnormalities are preceded by a massive acute phase response induced by saturated but not unsaturated fat or medium-chain fat, originating in mesenteric lymph nodes (MLNs). MLNs undergo dramatic expansion and contain numerous lipid-laden macrophages. In peritoneal macrophages incubated with chyle, Angptl4 dramatically reduced foam cell formation, inflammatory gene expression, and chyle-induced activation of ER stress. Induction of macrophage Angptl4 by fatty acids is part of a mechanism that serves to reduce postprandial lipid uptake from chyle into MLN-resident macrophages by inhibiting triglyceride hydrolysis, thereby preventing macrophage activation and foam cell formation and protecting against progressive, uncontrolled saturated fat-induced inflammation
Original languageEnglish
Pages (from-to)580-592
JournalCell Metabolism
Volume12
Issue number6
DOIs
Publication statusPublished - 2010

Keywords

  • endoplasmic-reticulum stress
  • mouse peritoneal-macrophages
  • angiopoietin-like protein-4
  • low-density lipoproteins
  • induced adipose factor
  • insulin-resistance
  • target gene
  • lipase
  • obesity
  • activation

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    Lichtenstein, L. L., Mattijssen, F. B. J., de Wit, N. J. W., Georgiadi, A., Hooiveld, G. J. E. J., van der Meer, R., He, Y., Qi, L., Köster, A., Tamsma, J. T., Tan, N. S., Müller, M. R., & Kersten, A. H. (2010). Angptl4 Protects against Severe Proinflammatory Effects of Saturated Fat by Inhibiting Fatty Acid Uptake into Mesenteric Lymph Node Macrophages. Cell Metabolism, 12(6), 580-592. https://doi.org/10.1016/j.cmet.2010.11.002