Atherosclerosis

We provide a large contract research program on energy metabolism in relation to obesity, type 2 diabetes, NASH and atherosclerosis. Within this field of expertise we offer custom-made drug and dietary intervention studies in our unique APOE*3-Leiden.CETP  mouse model, a well-established model for human-like lipid metabolism and atherosclerosis.

Dyslipidemia and atherosclerosis

  • Main advantage over other dyslipidemic models is that APOE*3-Leiden.CETP mice respond to lipid-lowering an HDL-increasing interventions similarly as humans.
  • Accomplished by its intact expression of apoE and the LDL receptor, and transgenic expression of human CETP.
  • In contrast, apoE-deficient and LDL receptor-deficient models do not respond to lipid-lowering interventions.
  • Develops diet-induced atherosclerotic lesions with all the characteristics of human lesions.

Main areas of expertise involving the APOE*3-Leiden.CETP mouse model:

  • Atherosclerosis
  • Diabetes and Obesity
  • Dyslipidemia
  • Energy expenditure, with a specific focus on the role of brown fat
  • Intestinal microbiota
  • Nonalcoholic steatohepatitis (NASH) / Nonalcoholic fatty liver disease (NAFLD)

Human-like pathologies in the APOE*3-Leiden.CETP model:

  • Dyslipidemia, with plasma lipid levels easily titrated to desired levels.
  • Insulin resistance, which develops on a high-fat diet.
  • NASH, with hepatic accumulation of lipids and inflammatory cells.
  • Atherosclerosis, driven by both cholesterol and inflammation.

Validated intervention strategies in the APOE*3-Leiden.CETP model:

  • Lipid-lowering strategies, with reduction of atherosclerosis (g. statins, PCSK9 inhibitors, fibrates).
  • HDL-raising strategies, with reduction of atherosclerosis (g. CETP inhibitors, niacin).
  • Anti-diabetic strategies, with improvement of insulin sensitivity (g. GLP1 analogs, rosiglitazone).
  • Brown fat activation, with reduction of obesity, dyslipidemia and atherosclerosis (g. β3-adrenergic receptor agonist, BMP7).

Selected references:

  • Berbée JFP et al. Brown fat activation reduces hypercholesterolemia and protects from atherosclerosis development. Nat Commun 2015; 6: 6356.
  • Kühnast S et al. Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin. Eur Heart J 2014; 36(1): 39-50.
  • Wang Y et al. Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. Br J Pharmacol 2014; 171(3):723-34
  • Kooijman S et al. Inhibition of the central melanocortin system decreases brown adipose tissue activity. J Lipid Res 2014; 55(10): 2022-32.
  • Bijland S et al. Fenofibrate increases very low density lipoprotein triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice. J Biol Chem 2010; 285(33): 25168-75.

Flyer APOE*3-Leiden.CETP model

Cardiovascular Disease