Hepatic lipase deficiency

Hepatic lipase (HL) is an enzyme that is made primarily by hepatocytes (and also found in adrenal gland and ovary) and hydrolyzes phospholipids and tr iglycerides of plasma lipoproteins. It is secreted and bound to the hepatoc yte surface and readily released by heparin. It is a member of the lipase s uperfamily and is homologous to lipoprotein lipase and pancreatic lipase. T he enzyme can be divided into an NH,terminal domain containing the catalyti c site joined by a short spanning region to a smaller COOH-terminal domain. The NH2-terminal portion contains an active site serine in a pentapeptide consensus sequence, Gly-Xaa-Ser-Xaa-Gly, as part of a classic Ser-Asp-His c atalytic triad, and a putative hinged loop structure covering the active si te. The COOH-terminal domain contains a putative lipoprotein-binding site. The heparin-binding sites may be distributed throughout the molecule, with the characteristic elution pattern from heparin-sepharose determined by the COOH-terminal domain. Of the three N-linked glycosylation sites, Asn-56 is required for efficient secretion and enzymatic activity. HL is hypothesized to directly couple HDL lipid metabolism to tissue/cellul ar lipid metabolism. The potential significance of the HL pathway is that i t provides the hepatocyte with a mechanism for the uptake of a subset of ph ospholipids enriched in unsaturated fatty acids and may allow the uptake of cholesteryl eater, free cholesterol, and phospholipid without catabolism o f HDL apolipoproteins. HL can hydrolyze triglyceride and phospholipid in all lipoproteins, but is predominant in the conversion of intermediate density lipoproteins to LDL a nd the conversion of post-prandial triglyceride-rich HDL into the postabsor ptive triglyceride-poor HDL. HL plays a secondary role in the clearance of chylomicron remnants by the l iver. Human post-heparin HL activity is inversely correlated with intermedi ate density lipoprotein cholesterol concentration only in subjects with a h yperlipidemia involving VLDL. This is consistent with intermediate-density lipoproteins being a substrate for HL. HDL cholesterol has been reported to be inversely correlated to HL activity, and on this basis it has been sugg ested that lowering HL would increase HDL cholesterol. However, the correla tion could also be due to a common hormonal factor such as estrogen, which has been shown to up-regulate apoAI and HDL cholesterol and lower HL. A str iking feature of severe deficiency of HL is the increase in HDL cholesterol and apolipoprotein AI and an approximately 10-fold increase in HDL triglyc eride. Hyper-alpha-triglyceridemia is not a feature of antiatherogenic HDL. HL binds not only to heparan, but also to the LDL receptor-related protein. It has been suggested that enzymatically inactive HL can play a role in he patic lipoprotein uptake, forming a "bridge" by binding to the lipoprotein and to the cell surface. This raises the interesting possibility that produ ction and secretion of mutant inactive HL could promote clearance of VLDL r emnants. We have described a rare family with HL deficiency. Affected patients are c om pound heterozygotes for a mutation of Ser267 to Phe that results in an i nactive enzyme and a mutation of Thr383 to Met that results in impaired sec retion and reduced specific activity. Human HL deficiency in the context of a second factor causing hyperlipidemia is strongly associated with prematu re coronary artery disease. Recently, it has been reported that mutations a ffecting the structure of HL (e.g., T383M) are relatively frequent in the F innish population. A C-to-T polymorphism in the promotor region of the HL g ene is associated with lowered HL activity and less strongly with increased HDL cholesterol. In summary, there is a good understanding of what HL does in lipoprotein me tabolism; however, there is little understanding of its physiological impor tance, that is, why HL does what it does. All of the current evidence consi stently suggests that HL deficiency is in a state of increased susceptibili ty to heart disease that requires the coexistence of an independent cause o f hyperlipidemia for the development of premature CAD. Any detrimental effe cts of high levels of HL are speculative at this time.