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      Feeding Angptl4(-/-) mice trans fat promotes foam cell formation in mesenteric lymph nodes without leading to ascites.

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          Abstract

          Angiopoietin-like 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting LPL. Inactivation of ANGPTL4 decreases plasma triglycerides and reduces the risk of coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of dyslipidemia and atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit lipid accumulation in the mesenteric lymph nodes (MLNs). In mice these pathological events exclusively unfold upon feeding a high saturated FA diet and are followed by an ultimately lethal pro-inflammatory response and chylous ascites. Here, we show that Angptl4(-/-) mice fed a diet rich in trans FAs develop numerous lipid-filled giant cells in their MLNs, yet do not have elevated serum amyloid and haptoglobin, do not exhibit ascites, and survive, unlike Angptl4(-/-) mice fed a saturated FA-rich diet. In RAW264.7 macrophages, the saturated FA, palmitate, markedly increased markers of inflammation and the unfolded protein response, whereas the trans-unsaturated elaidate and the cis-unsaturated oleate had the opposite effect. In conclusion, trans and saturated FAs have very distinct biological effects in macrophages. Furthermore, lipid accumulation in MLNs is uncoupled from activation of an acute-phase response and chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for dyslipidemia.

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          Author and article information

          Journal
          J. Lipid Res.
          Journal of lipid research
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1539-7262
          0022-2275
          Jun 2017
          : 58
          : 6
          Affiliations
          [1 ] Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
          [2 ] Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, MI.
          [3 ] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Lipidomics Core Facility, University of Cologne, Cologne, Germany.
          [4 ] School of Biological Sciences and Lee Kong Chian School of Medicine, Nanyang Technological University, Institute of Molecular and Cell Biology, Agency for Science Technology and Research, and KK Research Centre, KK Women's and Children's Hospital, Singapore.
          [5 ] Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands sander.kersten@wur.nl.
          [6 ] Division of Nutritional Sciences, Cornell University, Ithaca, NY.
          Article
          jlr.M074278
          10.1194/jlr.M074278
          5454507
          28412693

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