Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages.
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.
Nutrigenomics Consortium, TI Food and Nutrition, 6700AN, Wageningen, The Netherlands.
Laeticia
L
Lichtenstein
Frits
F
Mattijssen
Nicole J
NJ
de Wit
Anastasia
A
Georgiadi
Guido J
GJ
Hooiveld
Roelof
R
van der Meer
Yin
Y
He
Ling
L
Qi
Anja
A
Köster
Jouke T
JT
Tamsma
Nguan Soon
NS
Tan
Michael
M
Müller
Sander
S
Kersten
D000210:Acute-Phase Reaction / Q000378:metabolism; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001201:Ascites / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D004041:Dietary Fats / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism / Q000493:pharmacokinetics*; D006652:Histological Techniques; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D008198:Lymph Nodes / Q000166:cytology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D004041:Dietary Fats; D005227:Fatty Acids