title: Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development.
abstract: OBJECTIVE
  Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in macrophages and examined the impact of Angptl4 on atherosclerosis development.
  
  
  RESULTS
  Macrophage activation elicited by pathogen-recognition receptor agonists decreased Angptl4 expression, whereas lipid loading by intralipid and oxidized low-density lipoprotein increased Angptl4 expression. Consistent with an antilipotoxic role of Angptl4, recombinant Angptl4 significantly decreased uptake of oxidized low-density lipoprotein by macrophages, via lipolysis-dependent and -independent mechanisms. Angptl4 protein was detectable in human atherosclerotic lesions and localized to macrophages. Transgenic overexpression of Angptl4 in atherosclerosis-prone apolipoprotein E*3-Leiden mice did not significantly alter plasma cholesterol and triglyceride levels. Nevertheless, Angptl4 overexpression reduced lesion area by 34% (P<0.05). In addition, Angptl4 overexpression decreased macrophage content (-41%; P<0.05) and numbers of monocytes adhering to the endothelium wall (-37%; P<0.01). Finally, plasma Angptl4 was independently and negatively associated with carotid artery sclerosis measured by 3-T MRI in subjects with metabolic syndrome and low-grade systemic inflammation.
  
  
  CONCLUSIONS
  Angptl4 suppresses foam cell formation to reduce atherosclerosis development. Stimulation of Angptl4 in macrophages by oxidized low-density lipoprotein may protect against lipid overload.
authors: Nutrition, Metabolism, and Genomics Group, Wageningen University, Wageningen, The Netherlands.
authors: Anastasia
authors: A
authors: Georgiadi
authors: Yanan
authors: Y
authors: Wang
authors: Rinke
authors: R
authors: Stienstra
authors: Nathanja
authors: N
authors: Tjeerdema
authors: Aafke
authors: A
authors: Janssen
authors: Anton
authors: A
authors: Stalenhoef
authors: J Adam
authors: JA
authors: van der Vliet
authors: Albert
authors: A
authors: de Roos
authors: Jouke T
authors: JT
authors: Tamsma
authors: Johannes W A
authors: JW
authors: Smit
authors: Nguan Soon
authors: NS
authors: Tan
authors: Michael
authors: M
authors: Müller
authors: Patrick C N
authors: PC
authors: Rensen
authors: Sander
authors: S
authors: Kersten
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053318:Apolipoprotein E3 / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000473:pathology; D016893:Carotid Stenosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D002460:Cell Line; D002633:Chemotaxis; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D053318:Apolipoprotein E3; D008024:Ligands; D008077:Lipoproteins, LDL; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D002784:Cholesterol
keywords: atherosclerosis; inflammation; lipoprotein lipase; lipoproteins; macrophages