Purpose and aim of our studies

Abnormal concentrations of lipids can result from changes in the production, conversion, or clearance of lipoprotein particles. Thus, although static measurements are important, they do not reveal the underlying mechanisms involved in the dysregulation of lipid disorders. Therefore, kinetic studies in humans have become an important tool of clinical research to quantitatively understand the dynamics of lipid metabolism in vivo. Recently de novo lipogenesis (DNL) in the liver and apo CIII as novel components as regulators of lipid metabolism has become hot targets. The contribution of DNL-derived lipids to triglyceride rich lipoproteins (TRL) has been neglected due to lack of sensitive methodology to measure DNL. Recent breakthrough data on the multifaceted role of apo CIII as a regulator of TRLs has raised the inhibition of apo CIII as an attractive novel target to reduce TRLs and to prevent cardiovascular disease in particular in people with diabetes.

Recently novel tools using stable isotopes that make it possible to follow the production, transfer and direct catabolism of lipoprotein particles and triglycerides in vivo have been developed. In these studies stable isotope kinetic studies are utilized with novel technology that allows to analyze enrichments of apolipoproteins labelled with leucine, imaging of ectopic fat depots using magnetic resonance spectroscopy and a comprehensive panel of biomarkers in blood and adipose tissues, to investigate crosstalk between adipose tissue, gut and the liver in the physiological conditions (fasting and feeding) as well as the dysfunction of these axes in obesity, NAFLD and diabetes. We combine kinetic data with novel proteomics and lipidomics protocols to allow pathway analyses.

Specific topics

To explore the effect of apo CIII loss of function mutations (LOF) and gain of function mutations (GOF) on the dynamics of TRLs in vivo and PNPLA 3 and TM6SF2 variants, known to be linked with liver steatosis, on hepatic lipid metabolism.

To elucidate the dynamic relationship between postprandial lipemia and fasting kinetics of VLDL metabolism in type 2 diabetes with a special focus on DNL and apo CIII.

To examine metabolic dysregulation of the adipose tissue, gut and liver axis in Type 2 and Type 1 diabetes with a special focus on the role of incretin hormones.