Angiopoietin‐like 4 Directs Uptake of Dietary Fat Away From Adipose During Fasting

Abstract

Misregulation of lipid metabolism has been implicated in numerous disease states including metabolic syndrome, diabetes mellitus, and atherosclerosis. Angiopoietin‐like 4 (ANGPTL4) is a fasting‐induced inhibitor of lipoprotein lipase (LPL) and regulator of plasma triglyceride metabolism. ANGPTL4 is expressed most highly in adipose tissue and liver, but is also expressed in several other tissues including heart and skeletal muscle, and is also present in the plasma. We used gene expression assays in combination with triglyceride clearance and lipase activity assays to examine the kinetics of Angptl4 induction in various tissues during a fasting time course and the effects of global ANGPTL4 deficiency on triglyceride uptake in mice. Angptl4 was strongly induced early in fasting (within 2 to 4 hours), and this induction was not attributable to circadian rhythms. Consistent with previous reports we found that plasma triglyceride levels in Angptl4–/− mice were lower than wild‐type littermate controls, but interestingly, this was only the case in the fasted state. Using chylomicrons containing 3H‐labeled triglycerides we found that Angptl4–/− mice deliver more triglycerides to adipose tissue than wild‐type mice. Again, this difference was only apparent in the fasted state as Angptl4–/− mice showed no significant differences in uptake compared to wild‐type mice in the refed state. Our data support a model where Angptl4 is induced early in fasting and acts locally to divert uptake of fatty acids and triglycerides away from adipose tissues and toward triglyceride‐fueled tissues such as heart and skeletal muscle.Support or Funding Information1R01HL130146‐01A1, NIH/NHLBI (Davies) 06/01/16–03/31/21