Apolipoprotein C-III inhibition to lower triglycerides: one ring to rule them all?

Metabolic choke points are shown at which apolipoprotein (apo) C-III—depicted in two-dimensional semi-circular form—probably affects triglyceride (TG)-rich lipoprotein metabolism. Circled plus (+) and minus (−) signs indicate metabolic steps that apo C-III either promotes or inhibits, respectively. Starting at the upper left (A), dietary fat from the intestine is packaged into chylomicrons (B), which include apo C-III on their surface; apo C-III may promote chylomicron secretion. On the right, TG of endogenous (i.e. hepatic) origin is packaged into very-low-density lipoprotein (VLDL), whose secretion is almost certainly promoted by apo C-III (E). In the plasma space, apo C-III inhibits: (i) lipoprotein lipase (LPL)—indicated in monomeric cartoon form—by impairing the hydrolysis of chylomicrons (C) into chylomicron remnants (D) and of VLDL (F) into intermediate-density lipoprotein (IDL) (G), which is ultimately remodelled into LDL; and (ii) hepatic uptake of TG-rich remnants (D). Interfering with apo C-III production reverses these effects, i.e. reduces secretion of TG-rich lipoproteins (E), increases hydrolysis of TG-rich lipoproteins by LPL (C and F) and permits hepatic removal of TG-rich remnants (D). Metabolic choke points are shown at which apolipoprotein (apo) C-III—depicted in two-dimensional semi-circular form—probably affects triglyceride (TG)-rich lipoprotein metabolism. Circled plus (+) and minus (−) signs indicate metabolic steps that apo C-III either promotes or inhibits, respectively. Starting at the upper left (A), dietary fat from the intestine is packaged into chylomicrons (B), which include apo C-III on their surface; apo C-III may promote chylomicron secretion. On the right, TG of endogenous (i.e. hepatic) origin is packaged into very-low-density lipoprotein (VLDL), whose secretion is almost certainly promoted by apo C-III (E). In the plasma space, apo C-III inhibits: (i) lipoprotein lipase (LPL)—indicated in monomeric cartoon form—by impairing the hydrolysis of chylomicrons (C) into chylomicron remnants (D) and of VLDL (F) into intermediate-density lipoprotein (IDL) (G), which is ultimately remodelled into LDL; and (ii) hepatic uptake of TG-rich remnants (D). Interfering with apo C-III production reverses these effects, i.e. reduces secretion of TG-rich lipoproteins (E), increases hydrolysis of TG-rich lipoproteins by LPL (C and F) and permits hepatic removal of TG-rich remnants (D).