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 triglycerides of plasma lipoproteins. It is secreted and bound to the hepatocyte surface and readily released by heparin. It is a member of the lipase superfamily and is homologous to lipoprotein lipase and pancreatic lipase. The enzyme can be divided into an NH2-terminal domain containing the catalytic 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 catalytic triad, and a putative hinged loop structure covering the active site. 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/cellular lipid metabolism. The potential significance of the HL pathway is that it provides the hepatocyte with a mechanism for the uptake of a subset of phospholipids enriched in unsaturated fatty acids and may allow the uptake of cholesteryl ester, free cholesterol, and phospholipid without catabolism of HDL apolipoproteins. HL can hydrolyze triglyceride and phospholipid in all lipoproteins, but is predominant in the conversion of intermediate density lipoproteins to LDL and the conversion of post-prandial triglyceride-rich HDL into the postabsorptive triglyceride-poor HDL. HL plays a secondary role in the clearance of chylomicron remnants by the liver. Human post-heparin HL activity is inversely correlated with intermediate density lipoprotein cholesterol concentration only in subjects with a hyperlipidemia 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 suggested that lowering HL would increase HDL cholesterol. However, the correlation 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 striking feature of severe deficiency of HL is the increase in HDL cholesterol and apolipoprotein AI and an approximately 10-fold increase in HDL triglyceride. 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 hepatic lipoprotein uptake, forming a "bridge" by binding to the lipoprotein and to the cell surface. This raises the interesting possibility that production and secretion of mutant inactive HL could promote clearance of VLDL remnants. We have described a rare family with HL deficiency. Affected patients are compound heterozygotes for a mutation of Ser267 to Phe that results in an inactive enzyme and a mutation of Thr383 to Met that results in impaired secretion and reduced specific activity. Human HL deficiency in the context of a second factor causing hyperlipidemia is strongly associated with premature coronary artery disease. Recently, it has been reported that mutations affecting the structure of HL (e.g., T383M) are relatively frequent in the Finnish population. A C-to-T polymorphism in the promotor region of the HL gene 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 metabolism; however, there is little understanding of its physiological importance, that is, why HL does what it does. (ABSTRACT TRUNCATED)