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Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into
Laeticia Lichtenstein1, Frits Mattijssen, Nicole J de Wit
1Nutrigenomics Consortium, TI Food and Nutrition, 6700AN, Wageningen, The Netherlands.
Abstract:
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.
Insights
Mice lacking Angptl4 develop severe inflammation and disease when fed saturated fat. Angptl4 protects against this by reducing lipid uptake into macrophages, preventing harmful inflammatory responses.
Area of Science:
- Lipid metabolism
- Immunology
- Chronic disease research
Background:
- Dietary saturated fat intake is associated with chronic diseases like cardiovascular disease.
- The lipoprotein lipase inhibitor Angptl4's role in dietary fat response is not fully understood.
Purpose of the Study:
- To investigate the function of Angptl4 in response to dietary saturated fat.
- To elucidate the mechanisms by which Angptl4 influences inflammation and lipid metabolism.
Main Methods:
- Studied mice models lacking Angptl4.
- Administered dietary saturated, unsaturated, and medium-chain fats.
- Analyzed mesenteric lymph nodes (MLNs) and peritoneal macrophages.
- Assessed inflammatory gene expression and ER stress markers.
Main Results:
- Mice lacking Angptl4 exhibited a lethal phenotype including peritonitis, ascites, fibrosis, and cachexia upon saturated fat consumption.
- Saturated fat induced a massive acute phase response originating in MLNs, characterized by lipid-laden macrophages.
- Angptl4 inhibited foam cell formation, inflammatory gene expression, and ER stress in macrophages exposed to chyle.
- Fatty acid induction of macrophage Angptl4 reduced triglyceride hydrolysis, limiting lipid uptake and preventing inflammation.
Conclusions:
- Angptl4 is crucial for preventing severe inflammatory disease induced by dietary saturated fat.
- Angptl4 acts by inhibiting triglyceride hydrolysis in macrophages, thereby reducing lipid accumulation and inflammation.
- Targeting Angptl4 may offer therapeutic strategies for managing chronic diseases linked to dietary fat intake.
