Molecular metabolism underlying hypertriglyceridemia From bench to bedside

This thesis explores the underlying biochemical mechanisms that explain the hypertriglyceridemic phenotype in type 2 diabetes mellitus (T2DM), an important factor for the increased risk for cardiovascular disorders. Two recently identified proteins involved in TG metabolism are central in this thesis: glycosylphosphatidyl inositol HDL binding protein (GPIHBP1) and sulfatase 2 (SULF2). Various in vivo studies both in human and mice model, and in vitro experiments using hepatic and endothelial cell lines were used.
GPIHBP1 is essential for LPL-mediated lipolysis where triglycerides are degraded to free fatty acids. We show that mutations in GPIHBP1 leads to loss of function of the protein, leads to hypertriglyceridemia and may be the underlying cause of high TG in T2DM. Here, we tested and show that GPIHBP1 expression in adipose tissue is associated with insulin resistance and leads to reduced LPL-mediated lipolysis. Furthermore, we also show that in general population, a genetic risk score is associated with CVD risk independent of metabolic syndrome, which is also associated with CVD risk.
SULF2 is a protein that interferes with the degree of sulfation of the heparan sulfate proteoglycans involved in the hepatic clearance of TG-rich lipoproteins. Here we show that genetic variant in SULF2 is associated with less SULF2 protein and an improved clearance of TG and thus support the interest for SULF2 as a target for intervention in T2DM. Furthermore, we also show in in vitro experiments that SULF2 expression and secretion is upregulated in insulin resistance state via the AKT2/IRS2 pathway.