Background: Elevated plasma triglycerides (TG) are increasingly recognized as a risk factor for atherosclerosis. A new adipocytokine was discovered by several groups which is referred to as Angptl4 (Angiopoietin-like protein 4). Angptl4 was recently identified as a major determinant of plasma TG levels in mice. Angptl4 is a 50 KDa secreted protein belonging to the family of fibrinogen/angiopoietin-like proteins. Objective/Design: In order to characterize the metabolic function of Angptl4, we explored dietary modulation effects on transgenic mice overexpressing Angptl4. Results: Taking advantage of the induction of Angptl4 by fasting, we showed that Angptl4 strongly inhibits LPL and HL activities. Later, we reported the development, validation and utilization of an ELISA assay to quantitatively assess Angptl4 levels in human plasma. Within an individual, Angptl4 levels rise in response to elevation of plasma free fatty acids. Furthermore, we address the function of Angptl4 in the heart. Dietary unsaturated fatty acids have a major impact on human health, which is likely achieved via changes in gene expression. Fatty acids regulate gene expression mainly via nuclear receptors, including the PPARs. Angptl4 appears to be regulated by dietary fat in a PPARb/d dependent, but in a PPARa independent way. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma TG-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. Finally we investigated the function of Angptl4 in the intestine. Elevated saturated fat consumption is associated with increased risk for numerous chronic diseases, including inflammatory bowel disease, and obesity. Besides carrying out nutrient digestion and absorption, the GI-tract also produces a variety of hormones that play pivotal roles in nutrient handling and energy homeostasis. We report that Angptl4 is fat sensitive hormone produced by enteroendocrines cells. Noticeably, chronic saturated fat feeding led to complex and dramatic phenotype in Angptl4-/- mice. Angptl4-/- fed saturated fat developed a severe pathology leading to death. This lethal phenotype is preceded by excessive inflammation as shown by a dramatic hepatic acute phase response. Conclusion: The data show that Angptl4 protects against the pro-inflammatory and ultimately lethal effects of chronic overconsumption of saturated fat.