OBJECTIVE: The pathophysiology of hypertriglyceridemia is complex hampering effective therapeutic strategies. Increased central parasympathetic nerve activity was shown to inhibit hepatic triglyceride (TG) excretion via modulation of liver stearyl-CoA desaturase (SCD)-1 activity in rodents. We evaluated the impact of 7-h lactate clamping on VLDL-TG homeostasis in humans. METHODS:Eight normolipidemic, male subjects were subjected to a continuous infusion of l-lactate (target concentration 3 mmol/L) or saline for 7 h in random order on two separate occasions. TG kinetics in very low density lipoproteins (VLDL1 and 2) were measured after a bolus injection of [1,1,2,3,3]-(2)H5-glycerol. Palmitic acid (16:0) and palmitoleic acid (16:1) in VLDL1 and VLDL2 were measured as a reflection of liver SCD1 activity. RESULTS:Plasma TG levels changed by 0.16 ± 0.09 mmol/L during lactate vs -0.15 ± 0.08 mmol/L during saline (P < 0.05). VLDL1 16:1/16:0 ratio increased to 1.2 ± 0.7 during lactate versus a decrease during saline by -1.5 ± 0.6 (p = 0.01). During lactate VLDL1-TG excretion was higher compared to saline (1604 [827-2870] versus 1285 [505-2155] μmol glycerol; p < 0.05), trending toward higher VLDL1-TG pool sizes during lactate (28%; p = 0.07 versus saline). CONCLUSIONS: In normolipidemic men, 7-h l-lactate clamp increases, rather than decreases SCD1 activity and hepatic TG secretion leading to elevated plasma TG levels. These conflicting data between human and rodents on central regulation of hepatic TG excretion illustrate that experimental findings on the role of the central nervous system in lipid metabolism should be interpreted with caution.
RCT Entities:
OBJECTIVE: The pathophysiology of hypertriglyceridemia is complex hampering effective therapeutic strategies. Increased central parasympathetic nerve activity was shown to inhibit hepatic triglyceride (TG) excretion via modulation of liver stearyl-CoA desaturase (SCD)-1 activity in rodents. We evaluated the impact of 7-h lactate clamping on VLDL-TG homeostasis in humans. METHODS: Eight normolipidemic, male subjects were subjected to a continuous infusion of l-lactate (target concentration 3 mmol/L) or saline for 7 h in random order on two separate occasions. TG kinetics in very low density lipoproteins (VLDL1 and 2) were measured after a bolus injection of [1,1,2,3,3]-(2)H5-glycerol. Palmitic acid (16:0) and palmitoleic acid (16:1) in VLDL1 and VLDL2 were measured as a reflection of liver SCD1 activity. RESULTS: Plasma TG levels changed by 0.16 ± 0.09 mmol/L during lactate vs -0.15 ± 0.08 mmol/L during saline (P < 0.05). VLDL1 16:1/16:0 ratio increased to 1.2 ± 0.7 during lactate versus a decrease during saline by -1.5 ± 0.6 (p = 0.01). During lactate VLDL1-TG excretion was higher compared to saline (1604 [827-2870] versus 1285 [505-2155] μmol glycerol; p < 0.05), trending toward higher VLDL1-TG pool sizes during lactate (28%; p = 0.07 versus saline). CONCLUSIONS: In normolipidemic men, 7-h l-lactate clamp increases, rather than decreases SCD1 activity and hepatic TG secretion leading to elevated plasma TG levels. These conflicting data between human and rodents on central regulation of hepatic TG excretion illustrate that experimental findings on the role of the central nervous system in lipid metabolism should be interpreted with caution.
Authors: Kasper W Ter Horst; Daniel F Vatner; Dongyan Zhang; Gary W Cline; Mariette T Ackermans; Aart J Nederveen; Joanne Verheij; Ahmet Demirkiran; Bart A van Wagensveld; Geesje M Dallinga-Thie; Max Nieuwdorp; Johannes A Romijn; Gerald I Shulman; Mireille J Serlie Journal: Diabetes Care Date: 2020-12-08 Impact factor: 17.152