The regulation of hepatic lipase activity
Creators: name: Ramsamy, Tanya A
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 2004
Subjects: subject: Chemistry, Biochemistry.

description: Human hepatic lipase (HL) is a 66-kDa glycoprotein that plays an important role in the metabolism of apoB-containing lipoproteins and high density lipoproteins (HDL). Both the lipid and apolipoprotein composition of lipoproteins have been shown to modulate HL activity. In this study, very low density lipoproteins (VLDL) were found to be the best lipoprotein substrates for HL followed by low density lipoproteins (LDL) and HDL. Only 1% of the fatty acids released from HDL3 by HL are derived from triglycerides (TG) whereas the remainder of fatty acids produced are from the lipolysis of diglycerides (DG (49%)) and phospholipids (PL (50%)). In order to further study the role of lipoprotein composition on HL activity, HDL and LDL fractions were isolated from subjects with familial combined hyperlipidemia (FCHL) and matched controls and used as substrates for the enzyme. HL-mediated hydrolysis of patient and control LDL and HDL fractions is similar despite elevated serum TG levels in subjects with FCHL. In both patient and control samples, the most buoyant LDL and HDL fractions are better substrates for HL than the corresponding denser fractions when normalized for total protein content. Although differences are observed in the acylglycerol and PL hydrolysis of the two patient groups, these differences are not related to the DG content of the lipoproteins. The association of HL with pure heparan sulfate proteoglycans (HSPG) has little effect on hydrolysis of HDL particles, but significantly inhibits (&gt;80%)the hydrolysis of LDL and VLDL. Lipolytic inhibition is associated with a differential ability of the lipoproteins to remove HL from the HSPG. LDL and VLDL are unable to displace HL, while HDL readily displaces the enzyme from the HSPG. This is consistent with the view that HSPG-bound HL is inactive. HDL also displaces HL from the surface of the hepatoma cell line, HepG2, and Chinese Hamster Ovary (CHO) cells stably overexpressing human HL. Purified apolipoprotein (apo) A-I is more efficient than HDL at liberating HL from both pure and cell surface HSPG. Furthermore, different HDL fractions vary in their abilities to displace the enzyme from the cell surface. The buoyant HDL2 has a greater capacity to remove HL from the cell surface and intracellular compartments when compared to the smaller denser HDL particles. Displacement of HL by apoA-I does not enhance the hydrolysis of VLDL. This somewhat paradoxical finding appears to result from the direct inhibition of HL by apoA-I, as both apoA-I and HDL are able to inhibit VLDL-lipid hydrolysis. The different HDL subspecies also uniquely affect the activity of the enzyme. A detailed evaluation of different HDL fractions shows that HDL2 stimulates HL-mediated hydrolysis of VLDL-TG, while the smaller HDL3 is inhibitory. Inhibition of VLDL hydrolysis appears to result from a decreased interlipoprotein shuttling of HL between VLDL and the smaller more dense HDL particles. These findings suggest that high HDL2 levels are positively related to efficient TG hydrolysis by their ability to enhance the liberation of HL into the plasma compartment and by a direct stimulation of VLDL-TG hydrolysis. Taken together, these results demonstrate that the lipid and apolipoprotein composition of lipoproteins, hence lipoprotein structure, in addition to interlipoprotein interactions are central to the regulation of HL activity.