The role of hepatic lipase in lipoprotein metabolism

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Abstract

Hepatic lipase (HL) is one of two major lipases released from the vascular bed by intravenous injection of heparin. HL hydrolyzes phospholipids and triglycerides of plasma lipoproteins and is a member of a lipase superfamily that includes 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 post-absorptive triglyceride-poor HDL. 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 Ser267Phe that causes an inactive enzyme and a mutation of Thr383Met that results in impaired secretion of HL and reduced specific activity. Human HL deficiency in the context of a second factor causing hyperlipidemia is strongly associated with premature coronary artery disease.

Introduction

Hepatic lipase (HL) is one of two major lipases released from the vascular bed by intravenous injection of heparin [1], the other being lipoprotein lipase (LPL). HL is distinguished from LPL by its resistance to inhibition by 1 M NaCl or protamine sulfate and the absence of a requirement for an apolipoprotein activator. HL is synthesized primarily by hepatocytes (and also found in adrenal gland and ovary) and hydrolyzes phospholipids and triglycerides of plasma lipoproteins. This discussion of HL will cover the structure and evolutionary neighbors of HL, the lipid and lipoprotein substrates of HL, the question of whether HL functions as a ‘bridge’ in lipoprotein uptake, the phenotype of the HL ‘knock out’, and finally future prospects for research into HL.

Section snippets

Normal HL structure

The amino acid sequence of mature human HL has been deduced from DNA sequence data to consist of 476 amino acids, comprising a protein with a calculated molecular weight of 53 431 Da [2], [3]. The human HL gene is on chromosome 15q21 and is 35 kilobases (kb) in size, with nine exons that encode a mRNA of 1.5 kb [4]. HL requires glycosylation at asparagine-56 for activity and secretion [5]. HL can be divided into two domains, an N-terminal domain that contains an Asp–His–Ser catalytic triad and

HL evolutionary neighbors

The cloning and sequencing of three major lipases, HL, LPL and pancreatic lipase made it clear that they constitute a family of homologous enzymes. A gapped BLAST 2.0 search [9] of the NIH sequence database identified HL as a member of a lipase family that includes LPL, pancreatic lipase, pancreatic lipase-related protein-1, pancreatic lipase-related protein-2 and hornet phospholipase A1, a distant relationship with fly yolk proteins was also noted (Fig. 2). The homology is highest with LPL and

Lipid and lipoprotein substrates of HL

HL hydrolyzes both phospholipid (PL) and triglyceride (TG). It functions as a phospholipase A1 and hydrolyzes fatty acids from the 1 and 3 positions of TG. It preferentially hydrolyzes phosphatidylethanolamine (PE) and phosphatidylcholine (PC) containing the unsaturated fatty acids linoleate and arachidonate [10]. Early studies by Nilsson and colleagues suggested that HL plays a special role in vivo in the partitioning and uptake of chylomicron and HDL phospholipids by the liver [11]. Because

Does HL have a ‘bridge’ function in the clearance of remnant lipoproteins?

The role of HL in the clearance of chylomicron remnants and VLDL remnants is not well established. This is perhaps because there appear to be multiple steps in the clearance of remnant lipoproteins by the liver. These have been well summarized and critically evaluated by Cooper [14]. The current concepts consist of a two-step process beginning with the sequestration of remnant lipoproteins in the liver Space of Disse by binding to heparan, LDL-receptor related protein (LRP) and/or HL. The

Human and mouse knock-outs of HL: redundancy or measuring the wrong phenotype?

We have studied a kindred with HL deficiency due to compound heterozygosity for mutations in HL [17], [18]. The mutation S267F (in which the wild-type serine is replaced by phenylalanine) results in an inactive enzyme, while the mutation T383M (in which the wild-type threonine is replaced by methionine) results in an enzyme that is poorly secreted from cells and has a low activity [19]. No other isolated HL deficiency of this magnitude has been reported in humans, making detection of complete

Heart disease in OHLD family members

The three compound heterozygotes (B1, B2 and B3) have had coronary artery disease. As mentioned, the proband B1 had a fatal MI at age 51. B2 was symptomatic with angina at age 50 with severe multiple vessel coronary atherosclerosis requiring coronary angioplasty at age 53. B2 then suffered a severe MI at age 58 despite treatment with lovastatin. Repeat angiography in B2 in 1992 revealed severe diffuse multiple vessel occlusive disease. Treatment includes lovastatin 80 mg daily. B3 had a history

ApoAI- and AII-containing lipoproteins in HL deficiency

The conversion of VLDL to LDL requires the loss of TG and surface constituents consisting of apolipoproteins C and E, PL and cholesterol [21]. This ‘excess’ surface material is transferred to the HDL fraction [21], [22] and preferentially contributes to the mass of HDL2.

HDL can be separated into particles containing apoAI and apoAII (AI,AII) and particles containing apoAI without apoAII (AI, desAII) [23]. The AI,AII and AI, des AII are equal acceptors of TG and PL during the metabolism of

Sunrise or sunset for HL?

The aggregate of the data available to date are consistent with HL having a modest catalytic role in determining the plasma concentration of remnant lipoproteins. However, the association of lower HL activity with higher remnant lipoprotein concentration appears to require an independent cause for elevation of VLDL and/or VLDL remnant lipoproteins. A significant amount of data point to HL playing a major role in HDL phospholipid and TG metabolism with the lipoprotein subclass defined as

Acknowledgements

The invaluable contributions of Dr J. Alick Little, Dr Robert A. Hegele, Camilla Vezina, Graham Maguire and Maureen Lee are gratefully acknowledged.

References (27)

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