Moreover, studies from overexpression or depletion of LPL in macrophages demonstrate that LPL promotes the binding and uptake of modified LDLs by macrophages and thus enhances foam cell formation 28, 29.

This suggests that ANGPTL4 is a critical regulator of macrophage functions. Angptl4 −/− mice develop severe inflammation and accumulate foam cells in the mesenteric lymph nodes when fed a diet high in saturated fat 27. ANGPTL4 is also highly abundant in macrophages and it is induced by dietary fatty acids 27. It's expression is regulated by fasting, PPARs, glucocorticoids, and hypoxia in a tissue-specific manner 23, 24, 25, 26. Although decreased lipid content is generally atheroprotective, E40K, a loss of function variant of ANGPTL4, was associated with increased coronary heart disease risk despite being associated with an atheroprotective lipid profile, suggesting that ANGPTL4 influences parameters beyond lipid levels 22.ĪNGPTL4 is highly expressed in adipose tissues, placenta, liver, kidney and heart in humans 23, 24. Interestingly, human studies have shown that a common sequence variant near the ANGPTL4 gene is associated with decreased plasma TGs and increased high-density lipoprotein cholesterol (HDL-C) levels, and ANGPTL4 expression is positively associated with metabolic parameters including levels of insulin, fatty acids and leptin 21. As a result, overexpression of ANGPTL4 in mice leads to hypertriglyceridemia, whereas deficiency leads to lowering of circulating lipids 20. Particularly, ANGPTL4 is a strong inhibitor of lipoprotein lipase (LPL), an enzyme that catalyses the hydrolysis of triglycerides (TG) from very LDL (VLDL) and chylomicrons, and regulates the uptake of circulating lipids into tissues 18, 19. In addition, ANGPTL4 has been shown maintains in vivo repopulation capacity of CD34+ human cord blood cells 12.ĪNGPTL4 is a multifunctional protein that regulates many metabolic and non-metabolic processes through its distinct N-terminal and C-terminal domains 13, 14, 15, 16, 17. Recent studies have shown that a family of proteins called angiopoietin-like proteins (ANGPTLs), particularly ANGPTL2 and ANGPTL5, are known to stimulate the expansion of haematopoietic stem cells ex vivo 9, 10, 11. Previous studies have demonstrated that hyperlipidemia-induced leukocytosis in different mouse models including Abca1 −/− or Abcg1 −/− and Apoe −/− mice is associated with the expansion and proliferation of haematopoietic stem and multipotential progenitor cells (HSPCs) in the bone marrow (BM) 6, 7, 8. Monocytosis and neutrophilia have been observed in animal models of atherosclerosis including pigs and rabbits, and seem to contribute to atherogenesis 4, 5. Apart from foam cells, the monocyte count in blood circulation independently predicts risk for coronary artery disease after adjustment for conventional risk factors 3. Furthermore, both macrophages and foam cells play a key role in mediating inflammatory response in athero-plaques. However, accumulation of large numbers of foam cells in the arterial wall leads to the generation of atherosclerotic plaques 1. Foam cell formation is a protective mechanism whereby the vessel wall rids itself of potentially harmful lipids. Here, monocytes differentiate into macrophages, scavenge Ox-LDL, accumulate neutral lipids and transform into foam cells 1, 2.

Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.ĭuring the early stages of atherosclerosis, modified lipoproteins, primarily oxidized low density lipoproteins (Ox-LDL) accumulate in the intima, and activate endothelial and smooth muscle cells, recruit circulating monocytes into the sub-endothelial layer. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis.

Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis.

Martin whatson beyond the wall