Liraglutide Increases the Catabolism of Apolipoprotein B100–Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression
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posted on 2021-02-02, 23:16 authored by Bruno Vergès, Laurence Duvillard, Jean Paul Pais de Barros, Benjamin Bouillet, Sabine Baillot-Rudoni, Alexia Rouland, Jean Michel Petit, Pascal Degrace, Laurent Demizieux<a><b>OBJECTIVE:</b></a> Dyslipidemia observed in type 2 diabetes (T2DM) is
atherogenic. Important features of diabetic dyslipidemia are increased levels
of triglyceride-rich lipoproteins and small dense LDL particles which, all have
apolipoprotein B100 (apoB100) as major apolipoprotein. This prompted us to
study the effect of the GLP1 agonist, liraglutide, on the metabolism of apoB100
containing lipoproteins.
<p><b>RESEARCH DESIGN AND METHODS</b>: We performed an <i>in vivo</i> kinetic study with stable isotopes (L-[1-<sup>13</sup>C]
leucine) in 10 T2DM patients before and after 6-month treatment with
liraglutide (1.2 mg/day). We also
evaluated, in mice, the effect of liraglutide on the expression of genes
involved in apoB100 containing lipoprotein clearance.</p>
<p><b>RESULTS</b>: In T2DM patients, liraglutide treatment significantly
reduced plasma apoB100 (0.93±0.13 vs. 1.09±0.11 g/L,
p=0.011) and fasting triglycerides (1.76±0.37 vs. 2.48±0.69 mmol/L, p=0.005). The kinetic study showed a
significant increase in indirect catabolism of VLDL<sub>1</sub>-apoB100
(4.11±1.91 vs. 2.96±1.61 day<sup>-1</sup>,p=0.005), VLDL<sub>2</sub>-apoB100
(5.17±2.53 vs. 2.84±1.65 day<sup>-1</sup>,p=0.008),
IDL-apoB100 (5.27±2.77 vs. 3.74±1.85 day<sup>-1</sup>,p=0.017)
and in catabolism of LDL-apoB100 (0.72±0.22 vs. 0.56±0.22 day<sup>-1</sup>,p=0.005). In mice, liraglutide
increased lipoprotein lipase (LPL) gene expression and reduced Proprotein
convertase subtilisin/kexin type 9 (PCSK9), Retinol Binding Protein 4 (RBP4)
and Tumor Necrosis Factor alpha (TNF alpha) gene expression in adipose tissue,
and decreased PCSK9 mRNA and increased LDL-receptor protein expression, in
liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the
liver.</p>
<p><b>CONCLUSIONS</b>: Treatment with liraglutide induces a significant
acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL<sub>1</sub>,
VLDL<sub>2</sub>, IDL) and LDL. Liraglutide modifies the expression of genes
involved in apoB100 containing lipoprotein catabolism. These positive effects
on lipoprotein metabolism may reduce cardiovascular risk in T2DM.</p>
