Dysregulated
lipoprotein metabolism is a major cause of atherosclerotic
cardiovascular disease (ASCVD). Use of stable
isotope tracers and compartmental modelling have provided deeper understanding of the mechanisms underlying
lipid disorders in patients at high risk of ASCVD, including
familial hypercholesterolemia (FH), elevated
lipoprotein(a) [Lp(a)] and
metabolic syndrome (MetS). In patients with FH, deficiency in
low-density lipoprotein (
LDL) receptor activity not only impairs the catabolism of
LDL, but also induces hepatic overproduction and decreases catabolism of
triglyceride-rich
lipoproteins (TRLs). Patients with elevated Lp(a) are characterized by increased hepatic secretion of Lp(a) particles. Atherogenic
dyslipidemia in MetS patients relates to a combination of overproduction of
very-low density lipoprotein-
apolipoprotein (
apo) B-100, decreased catabolism of apoB-100-containing particles, and increased catabolism of
high-density lipoprotein-
apoA-I particles, as well as to impaired clearance of TRLs in the postprandial state. Kinetic studies show that
weight loss,
fish oils,
statins and
fibrates have complementary modes of action that correct atherogenic
dyslipidemia. Defining the kinetic mechanisms of action of
proprotein convertase subtilisin/kexin type 9 and
angiopoietin-like 3 inhibitors on
lipid and
lipoprotein mechanism in dyslipidemic subjects will further our understanding of these
therapies in decreasing the development of ASCVD. "Everything changes but change itself. Everything flows and nothing remains the same... You cannot step twice into the same river, for other waters and yet others go flowing ever on." Heraclitus (c.535- c. 475 BCE).