Abstract 181: The Use of Recombinant Human Lipoprotein Lipase as a Treatment for Hypertriglyceridemia

Abstract

Pancreatitis affects 270,000 number of people a year in the US and has a mortality rate of approximately 5%. Hypertriglyceridemia is a well established risk factor for acute pancreatitis, accounting for 10% of cases. To investigate recombinant human lipoprotein lipase (rhLPL) as a potential therapy for pancreatitis caused by hypertriglyceridemia, we examined effect of rhLPL produced in CHO cells on lipoproteins in human plasma and hypertriglyceridemic mice. IV injection of 500 μL of 20% Intralipid into mice increased plasma TG levels over 200-fold to about 6000 mg/dL at 15 min. When mice were co-injected with rhLPL (2.5 μg/g BW; IV), TG levels reached 2200 mg/dL and by 3 h were completely normal unlike control animals, which took 24 hours. Plasma TGs were decreased by 81% and 63% compared to control mice when rhLPL was administered IV at a dose 2 μg/g BW and 1 μg/g BW consecutively for mice treated IP with 1 mL of 20% Intralipid. The effect of rhLPL was sustained for 6 hours for high dose rhLPL. Enhanced lipolysis from rhLPL treatment resulted in a 2-fold increase of plasma FFA, but the albumin binding capacity for FFA did not appear to be exceeded because all FFA were bound to either lipoproteins or albumin. Moreover, no pathological changes were observed in the pancreas of treated mice, as assessed by histology. Amylase levels in rhLPL treated mice given Intralipid at 6 h were increased only 1.4-fold, whereas in control mice 2.8-fold. Addition of rhLPL in vitro (2 μg per 250 μL of human plasma) resulted in a significant decrease in lipoprotein particle numbers of all subpopulations of VLDL, small LDL, and small HDL, whereas a significant increase was observed for large LDL and large HDL particle number. The sizes of VLDL shifted towards smaller particles and the opposite was observed for LDL and HDL particles. Overall, there was a 57% reduction of TGs in plasma treated with rhLPL. In summary, rhLPL at relatively low doses accelerates the clearance of TG-rich lipoproteins in mice after a fat load. It does so without causing accumulation of toxic levels of FFA in plasma and reduces hypertriglyceridemia induced markers of pancreatitis. Furthermore, observed changes in human lipoprotein subpopulation distribution after rhLPL treatment are positive in terms of atherosclerosis risk.