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 acute-phase response in mice.
Highlights
Angiopoietin-like protein (ANGPTL)4 regulates plasma lipids, making it an attractive target for correcting dyslipidemia
We previously suggested that enhanced LPL-mediated lipid uptake in macrophages may be at the basis of the mesenteric lymphadenopathy in Angptl4 / mice fed a high fat diet [29]
We addressed two independent questions relevant to the mesenteric lymphadenopathy phenotype in Angptl4 / mice fed a high fat diet: 1) what is the influence of endogenous ANGPTL4 on lipid uptake and utilization in macrophages; and 2) what is the role of N-terminal ANGPTL4 in the development of mesenteric lymphadenopathy, inflammation, and ascites?
Summary
Angiopoietin-like protein (ANGPTL) regulates plasma lipids, making it an attractive target for correcting dyslipidemia. We studied the role of ANGPTL4 in lipid uptake in macrophages and in the above-mentioned pathologies using Angptl4-hypomorphic and Angptl4 / mice. ANGPTL4 deficiency did not alter LPL protein levels in macrophages. 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. ANGPTL4 deficiency increases lipid uptake and respiration in macrophages without affecting LPL protein levels. 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.
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