GLP-1 receptor agonist decreases VLDL-induced lipid accumulation in cardiomyocyte
J H Chang, H C LeeAbstract
Background/Introduction
Very low-density lipoprotein (VLDL), which carries lipids with the majority of triglycerides, is associated with cardiometabolic diseases. VLDL is internalised into cardiomyocytes via a specific receptor (VLDLR), which coordinates lipoprotein lipase (LPL) activity for the release of free fatty acids from VLDL. Excess VLDL induces lipid accumulation and results in lipotoxicity in cardiomyocytes. Glucagon-like peptide receptor agonist (GLP-1 RA), a medication used to treat type 2 diabetes mellitus, exhibits protective effects against cardiometabolic diseases. Mechanism remains largely undetermined.
Purpose
This study aimed to test the hypothesis that GLP-1 RA can modulate LDL activity and affect VLDL-induced lipid accumulation.
Methods
Isolated and purified 25 μg/mL VLDL was used to incubate murine atrial myocytes (HL-1) with or without 100 nM GLP-1 RA (6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline, DMB). BODIPY staining and immunofluorescence imaging were used to quantify intracellular lipid content. Membrane proteins were isolated separately, and western blotting was used to determine protein expression. LPL ELISA and activity assays were used to determine expression levels and activity.
Results
VLDL incubation significantly increased intracellular lipid accumulation in HL-1 cells by 2.148 ± 0.127 folds (P= 0.0024) compared to the control group, as shown by BODIPY staining. DMB, the GLP-1 RA in the treatment group, significantly attenuated VLDL-induced lipid accumulation by 0.550 ± 0.196 folds (P=0.0057) compared to the VLDL group. The membranous V-LDL receptor (V-LDLR) expression, which was enhanced with VLDL incubation, was decreased by 0.823 ±0.019 folds (P<0.0001) in the GLP-1 RA group. However, LPL activity, which was quantified and standardised in cell homogenate, did not change after 24 h of treatment. The time course of GLP-1 RA effect on LPL was further examined at 3, 6, 12, 24, and 48 h. The results showed that the effect of DMB on LPL concentration peaked at 24 h (0.379 ± 0.707 folds compared to the VLDL group, P<0.0001).
Conclusions
GLP-1 RA decreased VLDL-induced lipid accumulation in HL-1 cells by affecting VLDLR membranous expression and LPL concentration. These findings suggest a novel mechanism underlying the cardioprotective effects of GLP-1 RA.Figure 1.