Objective: Postprandial dyslipidemia, a condition commonly presented in individuals with type 2 diabetes (T2D), is characterized by the overproduction of triglyceride (TG)-rich lipoproteins (TRL). This results in excess atherogenic chylomicron (CM) remnants in circulation, significantly increasing the risk of cardiovascular disease (CVD). Using a Syrian golden hamster model, our laboratory has revealed that intestinal hormone glucagon-like peptide-2 (GLP-2) regulates dietary fat uptake and increases CM production in insulin-resistant states. However, the mechanisms by which GLP-2 enhances CM production remain unclear. Previous studies have implicated nitric oxide (NO) in the actions of GLP-2, demonstrating the requirement of NO in CM secretion. Therefore, this study investigated the role of neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and CM formation.
Methods: nNOS-/- and C57BL/6 (WT) mice received an intraduodenal injection of olive oil, followed by an acute intraperitoneal (i.p.) injection of GLP-2 (0.25mg/kg; n=7) or vehicle (PBS; n=8). Blood samples were collected over a 2-hour period to assess postprandial lipid accumulation, and TRL fractions were isolated via ultracentrifugation. Immunoblotting was used to measure plasma apolipoprotein B48 (apoB48) protein expression.
Results: While GLP-2-treated WT mice showed characteristic rises in postprandial TG and cholesterol in whole plasma and TRL fractions, the effect of GLP-2 in nNOS-/- mice was abolished. The effect of GLP-2 on postprandial plasma apoB48 protein expression was also abolished in nNOS-/- mice relative to GLP-2-treated WT mice.
Conclusions: These findings demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and CM production in the postprandial state. Understanding this pathway will provide insight for future therapeutic interventions to treat lipid disorders in T2D.
E.M. Grande: None. K. Adeli: None.
Canadian Institutes of Health Research