Structure and activity of rat pancreatic lipase-related protein 2. Hepatic lipase mediates an increase in selective uptake of high-density lipoprotein-associated cholesteryl esters by human Hep 3B hepatoma cells in culture. A 2-methyleneoxetane analog of orlistat demonstrating inhibition of porcine pancreatic lipase. Rx drugs

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J Biol Chem. 1998 Nov 27;273(48):32121-8.
Structure and activity of rat pancreatic lipase-related protein 2.

Roussel A, Yang Y, Ferrato F, Verger R, Cambillau C, Lowe M.

Architecture et Fonction des Macromolecules Biologiques, CNRS-IFR1 UPR 9039, 31 Chemin Joseph Aiguier, 13402 Marseille cedex 20, France.

The pancreas expresses several members of the lipase gene family including pancreatic triglyceride lipase (PTL) and two homologous proteins, pancreatic lipase-related proteins 1 and 2 (PLRP1 and PLRP2). Despite their similar amino acid sequences, PTL, PLRP1, and PLRP2 differ in important kinetic properties. PLRP1 has no known activity. PTL and PLRP2 differ in substrate specificity, bile acid inhibition, colipase requirement, and interfacial activation. To begin understanding the structural explanations for these functional differences, we solved the crystal structure of rat (r)PLRP2 and further characterized its kinetic properties. The 1.8 A structure of rPLRP2, like the tertiary structure of human PTL, has a globular N-terminal domain and a beta-sandwich C-terminal domain. The lid domain occupied the closed position, suggesting that rPLRP2 should show interfacial activation. When we reexamined this issue with tripropionin as substrate, rPLRP2 exhibited interfacial activation. Because the active site topology of rPLRP2 resembled that of human PTL, we predicted and demonstrated that the lipase inhibitors E600 and tetrahydrolipstatin inhibit rPLRP2. Although PTL and rPLRP2 have similar active sites, rPLRP2 has a broader substrate specificity that we confirmed using a monolayer technique. With this assay, we showed for the first time that rPLRP2 prefers phosphatidylglycerol and ethanolamine over phosphatidylcholine. In summary, we confirmed and extended the observation that PLRP2 lipases have a broader substrate specificity than PTL, we demonstrated that PLRP2 lipases show interfacial activation, and we solved the first crystal structure of a PLRP2 lipase that contains a lid domain.

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Atherosclerosis. 1998 Dec;141(2):273-85.
Hepatic lipase mediates an increase in selective uptake of high-density lipoprotein-associated cholesteryl esters by human Hep 3B hepatoma cells in culture.

Rinninger F, Mann WA, Kaiser T, Ahle S, Meyer N, Greten H.

Universitat Hamburg, Krankenhaus Eppendorf, Medizinische Kernklinik und Poliklinik, Germany.

Selective uptake of high-density lipoprotein- (HDL-) associated cholesteryl esters (CE), i.e. lipid uptake independent from particle uptake, delivers CE to the liver and steroidogenic tissues in vivo. In vitro, besides hepatocytes and steroidogenic cells many other cell types selectively take up HDL CE. Hepatic lipase (HL) stimulates the internalisation of apoprotein (apo) B-containing lipoproteins by hepatocytes independent from lipolysis. In this study the role of HL in the hepatic metabolism of apo A-I-containing lipoproteins, i.e. HDL, was investigated. HDL3 (d = 1.125-1.21 g/ml) was radiolabeled in its protein (125I) and in its CE moiety ([3H]cholesteryl oleyl ether, ([3H]CEt)). HL originated from tissue culture media of hepatoma cells and from post-heparin plasma. Human Hep 3B hepatoma cells incubated in medium containing radiolabeled HDL3. In the absence of HL, the rate of apparent HDL3 particle uptake according to the lipid tracer ([3H]CEt) was in most cases in approximately 10-fold excess on that due to the protein label (125I), indicating selective CE uptake from HDL3. Addition of HL to these incubations increased the cellular uptake of [3H]CEt and of 125I from HDL3 and quantitatively the most prominent effect was an up to approximately 2.5-fold stimulation of apparent selective CE uptake ([3H]CEt-125I). This increase in selective CE uptake was observed in the presence of tetrahydrolipstatin, an inhibitor of the catalytically active site of HL, suggesting that this HL effect is independent from lipolysis. HL binds to cell surface heparan sulfate proteoglycans. To explore the role of these molecules for the HL effect on selective CE uptake, hepatoma cells were depleted of proteoglycans or Chinese hamster ovary (CHO) cells deficient in proteoglycan synthesis were used. Proteoglycan-deficiency reduced the HL-mediated increase in selective uptake by more than 80%. To investigate if low-density lipoprotein (LDL) receptors or the LDL receptor-related protein (LRP) are involved in the HL effect on selective CE uptake, murine embryonic fibroblasts (MEF) were used which are deficient in these receptors; alternatively, monensin, an inhibitor of endocytosis was present in the medium of Hep 3B cells during the uptake assay for labeled HDL3. These experiments yielded no evidence for a role of LDL receptors or LRP in the HL-mediated increase in selective CE uptake. In summary, HL mediates an increase in HDL3 selective CE uptake by human Hep 3B hepatoma cells. This HL effect is independent from lipolysis and independent from LRP and LDL receptors. However this HL effect is susceptible to cell surface proteoglycan deficiency. The potential physiologic implication is that HL modifies HDL selective CE uptake by the liver in vivo and such an effect could play a role in reverse cholesterol transport.

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Bioorg Med Chem Lett. 1998 Apr 21;8(8):977-8.
A 2-methyleneoxetane analog of orlistat demonstrating inhibition of porcine pancreatic lipase.

Dollinger LM, Howell AR.

Department of Chemistry, University of Connecticut, Storrs 06269-4060, USA.

The 2-methyleneoxetane analog 2 of orlistat (OLS, 1) has been synthesized and tested against porcine pancreatic lipase (PPL). Despite the loss of the carbonyl group, a potential site for hydrogen bonding interaction with the enzyme and the key element in the acylation by OLS, 2 has activity comparable to 1.

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