The role of hepatic lipase in lipoprotein metabolism
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.
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2021, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsResponse of fatty acids and lipid metabolism enzymes during accumulation, depuration and esterification of diarrhetic shellfish toxins in mussels (Mytilus galloprovincialis)
2020, Ecotoxicology and Environmental SafetyCitation Excerpt :LPL and HL are important catalytic enzymes involved in lipoprotein metabolism. The former catalyzes the hydrolysis of the triacylglycerol component of circulating chylomicrons and very low density lipoproteins to provide free fatty acids and glycerol for incorporation in tissue (Mead et al., 2002), while HL hydrolyzes both phospholipids and triglycerides (Connelly, 1999). When mussels are starved, as occurred during toxin depuration in the present study (Svensson, 2003), fatty acids would be produced by the catalysis of LPL or HL enzymes to maintain their energy requirements.
An automated method for measuring lipoprotein lipase and hepatic triglyceride lipase activities in post-heparin plasma
2018, Clinica Chimica ActaCitation Excerpt :We do not know the reason for these discrepancies yet, but need to determine whether they are based on gene mutations or by other factors such as the presence of GPIHBP1 auto antibodies [27]. There are many reports on the discrepancy between lipase activity and concentration due to the structural modification of lipases by gene mutations [28–36]. These cases exhibited comparatively high concentrations of LPL and HTGL with little or no activity because of loss of function with gene mutation.
The role of plasma lipoprotein lipase, hepatic lipase and GPIHBP1 in the metabolism of remnant lipoproteins and small dense LDL in patients with coronary artery disease
2018, Clinica Chimica ActaCitation Excerpt :In particular, we paid attention to the HTGL concentration in pre-heparin and post-heparin plasma and discussed the role of HTGL on the metabolism of RLP-C and sdlDL-C in CAD patients. The increased [37,38] and decreased [39–41] HTGL concentration associated with CAD has been reported by different researchers during the last decades. Those discrepancy may be caused of the lack of the assay capable of measuring non-heparin plasma HTGL concentration.
A new enzyme-linked immunosorbent assay system for human serum hepatic triglyceride lipase
2017, Journal of Lipid ResearchCitation Excerpt :However, it is difficult to recruit large numbers of study subjects because of the rarity of this disease. Indeed there have been very few reports regarding this issue from North America and Northern Europe (26–28). Another approach would be a cohort study to investigate how baseline HTGL level is correlated with the future incidence of CVD.