Probing the role and regulation of plasma ANGPTL4 in mouse and human: a potential biomarker for metabolic syndrome

Over the next few decades obesity and its complications are expected to become an increasing burden on societies worldwide. Much research has been carried out investigating the molecular mechanisms that could explain the connection between obesity and its metabolic complications. While major progress has been made, it has become clear that further understanding of the link between obesity and its metabolic consequences is difficult without additional basic insight into how metabolism is governed at the biochemical, physiological, and hormonal level. The present research proposal should be placed within the context of identifying key hormonal regulators of nutrient metabolism, characterizing their biological function in cellular metabolism and energy homeostasis, and exploring their potential role in the metabolic syndrome in humans. Lately, a major focus has been on signaling molecules secreted by adipose tissue referred to as adipokines. An adipokine that has kept a relatively low profile is Angptl4, a secreted protein of about 50 kDa belonging to the family of Angiopoietin-like proteins. Evidence abounds that Angptl4 plays a major role in the regulation of lipid metabolism. Angptl4 inhibits the enzyme lipoprotein lipase (LPL), thereby suppressing clearance of triglyceride(TG)-rich lipoproteins and thus raising plasma TG levels. While inhibition of LPL and stimulation of adipose tissue lipolysis by Angptl4 are well supported, the overall role of Angptl4 in the physiological regulation of fuel selection as well as its impact on cellular metabolism is poorly understood. The first part of the proposal will address these two specific issues. Preliminary data support a major modulating role for Angptl4 in diet-induced obesity. Whereas on a low fat diet Angptl4-/- mice display a relatively mild phenotype, on a high fat diet Angptl4-/- mice become cachectic and develop ascites and peritonitis. The second part of the proposal aims to uncover the specific roles of Angptl4 in liver, intestine, and adipose tissue that underlie the observed clinical abnormalities. Finally, very limited information is available about Angptl4 in human. Due to the absence of an assay to quantitatively assess Angptl4 levels in human blood plasma, very little is known about the physiological determinants of plasma Angptl4 as well as the impact of specific disease conditions. In the third part of this proposal we will explore the physiological determinants of plasma Angptl4 levels in humans and determine to what extent plasma Angptl4 levels are altered by obesity or in type 2 diabetic patients, using a recently developed Angptl4 Elisa assay. Further elucidation of the regulation and functional role of Angptl4 in mouse and human will contribute to better understanding of the physiological regulation of nutrient homeostasis, which in turn is instrumental for exposing the mechanisms underlying specific features of the metabolic syndrome. The newly acquired knowledge may open up novel therapeutic opportunities for specific metabolic and/or gastrointestinal diseases. Additionally, plasma Angptl4 may have potential as a biomarker for these and other clinical conditions.