Characterization of ANGPTL4 function in macrophages and adipocytes using Angptl4-knockout and Angptl4-hypomorphic mice

Abstract

Elevated plasma triglyceride levels are increasingly considered as an independent risk factor for cardiovascular diseases (1-3). Triglycerides circulate in the blood in two major forms: as chylomicrons carrying the dietary triglycerides and as very low density lipoproteins carrying endogenously produced triglycerides (4). The clearance of plasma triglycerides is primarily mediated by the action of LPL. This secretory enzyme is produced by parenchymal cells of fat tissue, skeletal muscle, and heart, as well as by macrophages. With the help of the endothelial protein, glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), LPL is transferred from the surface of the sub-endothelial myocytes and adipocytes to the luminal side of the capillary endothelium. There, LPL hydrolyzes the triglycerides contained in the triglyceride-rich lipoproteins to release fatty acids for uptake by the underlying tissues (5-8). The activity of LPL is regulated posttranslationally by numerous factors, many of which are produced in the liver, including several apolipoproteins. In addition, LPL activity is governed by several members of the family of angiopoietin-like proteins (ANGPTLs): ANGPTL3 (9), ANGPTL4 (10-12), and ANGPTL8 (13-15). ANGPTL3 is produced in the liver and cooperates with ANGPTL8 to inhibit LPL activity in peripheral tissues Abstract Angiopoietin-like protein (ANGPTL)4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia. However, ANGPTL4 inactivation in mice fed a high fat diet causes chylous ascites, an acute-phase response, and mesenteric lymphadenopathy. Here, we studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4 / mice. Angptl4 expression in peritoneal and bone marrow-derived macrophages was highly induced by lipids. Recombinant ANGPTL4 decreased lipid uptake in macrophages, whereas deficiency of ANGPTL4 increased lipid uptake, upregulated lipid-induced genes, and increased respiration. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. Angptl4-hypomorphic mice with partial expression of a truncated N-terminal ANGPTL4 exhibited reduced fasting plasma triglyceride, cholesterol, and NEFAs, strongly resembling Angptl4 / mice. However, during high fat feeding, Angptl4-hypomorphic mice showed markedly delayed and attenuated elevation in plasma serum amyloid A and much milder chylous ascites than Angptl4 / mice, despite similar abundance of lipid-laden giant cells in mesenteric lymph nodes. In conclusion, ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. Compared with the absence of ANGPTL4, low levels of N-terminal ANGPTL4 mitigate the development of chylous ascites and an acutephase response in mice.-Oteng, A-B.

Transcriptome sequencing supports a conservation of macrophage polarization in fish

“…Growth factor in early stages of wound healing. Promotes dermal repair, angiogenesis and is expressed by anti-inflammatory macrophages 73 , 74 7.8 129.2 angptl4 Angiopoietin-like 4 00035942 00049924 4.1 3.9 Downregulated by TLR-stimulation in macrophages, prevents the formation of lipid-laden giant cells 75 and associated with anti-inflammatory macrophages 76 , 77 20.1 20.6 260.6 244.3 steap4 Six-transmembrane epithelial antigen of prostate 4 00042005 3.8 Metalloreductase involved in the transfer of ions from Fe 3 + and Cu 2 + to NAD and plays a role in cellular homeostasis during inflammation. Increased Steap4 may reduce circulating iron available for parasites 27 6.8 100.6 ppap2b or plpp3 Phosphatidic acid phosphatase type 2B/ Phospholipid phosphatase 3 00003642 00045370 3.8 3.7 Lysophosphatidic acid (LPA) inhibitor.…”

“…Data are of n = 3 fish. 1 Mills et al, 2000, 28 Mazzon et al, 2012, 52 Chen et al, 2001, 53 Chen and Lau, 2009, 54 Orecchioni et al, 2019, 55 Martinez and Gordon, 2014, 56 Nadella et al, 2015, 57 Sun and Kaartinen., 2018, 58 McLatchie et al, 1998, 59 Chen et al, 2011, 60 Pang et al, 2013, 61 Rogers et al, 2017, 62 Chen et al, 2019, 63 Broz et al, 2019, 64 Munder et al, 1999, 65 Jin et al, 2005, 66 Hertz et al, 2009, 67 Yang et al, 2017, 68 Stockmann et al, 2011, 69 Roszer et al, 2015, 70 Espina et al, 2013, 71 Das et al, 2018, 72 Eichelbaum and Krijgsveld, 2014, 26 Mantovani et al, 2019, 73 Shirakata et al, 2005, 74 Edwards et al, 2009, 75 Oteng et al, 2019, 76 Feingold et al, 2009, 77 Cho et al, 2019, 27 Scarl et al, 2017, 78 Wary and Humtsoe 2005, 79 Gustafsson et al, 2008, 80 Panchatcharam et al, 2014, 40 Carmans et al, 2010, 41 Loomis et al, 2019, 81 Della Fazia et al, 1997, 51 Ahmed and Prigent, 2017.…”

“…Mantovani et al, 2019,73 Shirakata et al, 2005,74 Edwards et al, 2009,75 Oteng et al, 2019,76 Feingold et al, 2009,77 Cho et al, 2019,27 Scarl et al, 2017,78 Wary and Humtsoe 2005,79 Gustafsson et al, 2008, …”

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

“…Another possible pathway mediating HDL-A-I atheroprotective function can be by raised expression of angiopoietin like-4 (ANGPTL-4), a known inhibitor of lipoprotein lipase [57] in endothelial cells: ANGPTL-4 reduces lipid uptake in macrophages [58]. By evaluating gene expression in whole genome microarrays, raised expression of ANGPTL-4 in EA-HY926 endothelial cells was found as one of the most up-regulated and biologically relevant molecules [59].…”

Cross-talk between ANGPTL4 gene SNP rs1044250 and weight management is a risk factor of Mets

“…In addition, the WC and waist-to-hip ratio is increased in adipocyte ANGPTL4 knockout mice [18]. Another research has found that the ANGPTL4 knockout mice fed with high-fat diet show granuloma lesions in intestine and WAT, as well as lymphangitis and mesenteric lymphadenitis [26,27], which suggests that ANGPTL4 is essential to the lymphatic drainage of lipids from WAT to the liver. A study has also reported that ANGPTL4 reduces appetite by inhibiting hypothalamic AMPK activity, accordingly, the ANGPTL4 knockout mice show increased appetite after fasting [28].…”