Time-Restricted Eating, ANGPTL4, and Reduction in Residual Cardiovascular Risk

Atherosclerotic cardiovascular disease treatment is being reevaluated, since a residual cardiovascular risk (RCR) persists even in patients who achieve optimal LDL-C values. Underlying causes are metabolic dysfunction, lipoprotein(a), inflammation, and triglyceride-rich lipoproteins and their remnants. Dietary treatment options like time-restricted eating (TRE) are becoming more widely acknowledged for their potential advantages in metabolic health and weight control, as a treatment of atherosclerosis expanding beyond LDL-C medication. Beyond weight loss, TRE (which restricts meals to a window of 6 to 8 h) appears as the most accessible treatment, and has been shown to improve blood pressure, lipid profiles, and glucose regulation through mechanisms like metabolic switching and circadian synchronization. We hypothesize, and will present our arguments, that a key mechanism underlying the cardiovascular and weight-related benefits of TRE is its impact on the circadian regulation of angiopoietin-like protein 4 (ANGPTL4) activity within adipose tissue. Additionally, lipolysis is accelerated by ANGPTL4 activation. TRE, via its actions on ANGPTL4, therefore not only inhibits adipose fatty acid uptake but stimulates their release as well. Additionally, TRE may increase intravascular very low-density lipoprotein (VLDL) catabolism by muscle due to the reduced exposure of lipoprotein lipase (LPL) to competing chylomicrons, known to slow the rate of VLDL catabolism. During the prolonged fasting, VLDL residence time is thus shortened, limiting the exposure to endothelium and hepatic lipases and thus reducing the amount of atherogenic remnant particles. Larger, longer-term randomized controlled studies in a variety of groups are required to further clarify TRE's function in RCR prevention and therapy. As knowledge of triglyceride lipoprotein (TRL) metabolism expands, a comprehensive strategy for the management of RCR emerges, and a broader spectrum of LPL regulator-based therapeutics is created. Consequently, it is advisable to prioritize further research into the influence of TRE on LPL modulation via ANGPTL4 and ANGPTL8, which provides a natural, accessible, and low-cost alternative.