Objective The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG >10 mmol/L) it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam. Methods The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored HDL-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls. Results In 46 patients (54%) rare DNA sequence variants were identified, comprising variants in LPL (n=19), APOC2 (n=1), APOA5 (n=2), GPIHBP1 (n=3) and LMF1 (n=8). In 22 patients (26%) only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype. Conclusion The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n=3), APOC2 (n=1) and APOA5 (n=2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis, and may help to guide future individualized therapeutic strategies.

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Objective Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodelling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here we sought to investigate the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM. Design and Methods Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype. Results Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; p=0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (p<0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P<0.05) and retinyl esters (RE) levels (P<0.001). Conclusions These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM.

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GPIHBP1 is a protein localized at the endothelial cell surface that facilitates triglyceride (TG) lipolysis by binding lipoprotein lipase (LPL). Whether Glycosyl Phosphatidyl Inositol high density lipoprotein binding protein 1 (GPIHBP1) function is impaired and may underlie the hyperTG phenotype observed in type 2 diabetes is not yet established. To elucidate the mechanism underlying impaired TG homeostasis in insulin resistance state we studied the effect of insulin on GPIHBP1 protein expression in human microvascular endothelial cells (HMVEC) under flow conditions. Next, we assessed visceral adipose tissue GPIHBP1 protein expression in type 2 diabetes Lepr db/db mouse model as well as in subjects with ranging levels of insulin resistance. We report that insulin reduces the expression of GPIHBP1 protein in HMVECs. Furthermore, GPIHBP1 protein expression in visceral adipose tissue in Lepr db/db mice is significantly reduced as is the active monomeric form of GPIHBP1 as compared to Leprdb/m mice. A similar decrease in GPIHBP1 protein was observed in subjects with increased body weight. GPIHBP1 protein expression was negatively associated with insulin and HOMA-IR.In conclusion, our data suggest that decreased GPIHBP1 availability in insulin resistant state may hamper peripheral lipolysis capacity.