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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 02.02.2021, 23:16 by Bruno Vergès, Laurence Duvillard, Jean Paul Pais de Barros, Benjamin Bouillet, Sabine Baillot-Rudoni, Alexia Rouland, Jean Michel Petit, Pascal Degrace, Laurent Demizieux
OBJECTIVE: 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.

RESEARCH DESIGN AND METHODS: We performed an in vivo kinetic study with stable isotopes (L-[1-13C] 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.

RESULTS: 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 VLDL1-apoB100 (4.11±1.91 vs. 2.96±1.61 day-1,p=0.005), VLDL2-apoB100 (5.17±2.53 vs. 2.84±1.65 day-1,p=0.008), IDL-apoB100 (5.27±2.77 vs. 3.74±1.85 day-1,p=0.017) and in catabolism of LDL-apoB100 (0.72±0.22 vs. 0.56±0.22 day-1,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.

CONCLUSIONS: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL1, VLDL2, 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.

Funding

The authors acknowledge grants from NovoNordisk and from the French National Research Agency (ANR) under the program “Investissements d’Avenir” with reference ANR-11-LABX-0021 (LipSTIC Labex). They also acknowledge financial support from the University of Burgundy-Franche-Comté, the National Institute of Health and Medical Research (Institut National de la Santé et de la Recherche Médicale [INSERM]), the Region Burgundy- Franche Comté and the Fonds Européens de Développement Régional.

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