Hepatic triglyceride content does not affect circulating CETP: lessons from a liraglutide intervention trial and a population-based cohort

Huub J van Eyk, Lisanne L Blauw, Maurice B Bizino, Yanan Wang, Ko Willems van Dijk, Renée de Mutsert, Johannes W A Smit, Hildo J Lamb, Ingrid M Jazet, Patrick C N Rensen, Huub J van Eyk, Lisanne L Blauw, Maurice B Bizino, Yanan Wang, Ko Willems van Dijk, Renée de Mutsert, Johannes W A Smit, Hildo J Lamb, Ingrid M Jazet, Patrick C N Rensen

Abstract

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (β: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (β: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (β: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (β: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Associations between hepatic triglyceride content and plasma CETP levels in the MAGNA VICTORIA study. Hepatic triglyceride content in relation to plasma CETP level, n = 47 (A), and change of hepatic triglyceride content in relation to change in plasma CETP level, liraglutide n = 21, placebo n = 23 (B). CETP: cholesteryl ester transfer protein.
Figure 2
Figure 2
Associations between hepatic triglyceride content and serum CETP concentrations in the NEO study population. Crude associations between hepatic triglyceride content and serum CETP concentration, stratified by sex (A) and lipid lowering drug use (B). Results were based on analyses weighted towards the BMI distribution of the general population (n = 1,611). CETP: cholesteryl ester transfer protein; NEO: Netherlands Epidemiology of Obesity.

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