Lipoprotein lipase inhibitor

Current available information does not permit definitive conclusions on the nature, specificity, and mechanism of action of the protein cofactor (s) of lipoprotein lipase. It is verj difiicult to correlate the observations described above (summarized in Table 10) since the enzyme preparations used were not pure or well characterized, and were derived from various sources. For instance, two species of lipoprotein lipase have been reported to exist in rat adipose tissue (G4), and major differences between enzymes of liver and adipose tissue have been noted (G16). Also, the nature of the apoprotein preparations employed as protein cofactor (s) of lipoprotein lipase has not been clearly specified in all the studies contaminated materials may account for the spurious results observed. At present, it is not known how apoproteins such as apo Glu, apo Ala, and apo Ser could exhibit their activator or inhibitor activity on lipoprotein lipase. If these different apoproteins indeed prove to be cofactors for lipoprotein lipase, the nature of the lipid-protein specificity must be established and thus the role played by carbohydrates, since some of these apoproteins are glycoproteins. 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

To increase the stability of milk products. Lipoprotein lipase is probably the most important in this regard as its activity leads to hydrolytic rancidity. It is extensively inactivated by HTST pasteurization but heating at 78°C x 10 s is required to prevent lipolysis. Plasmin activity is actually increased by HTST pasteurization due to inactivation of inhibitors of plasmin and/or of plasminogen activators. 

Downey (1980) reasoned that although milk lipoprotein lipase is present in sufficient amounts to cause extensive hydrolysis and potential marked flavor impairment, this does not happen in practice for the following reasons (1) the fat globule membrane separates the milk fat from the enzyme, whose activity is further diminished by (2) its occlusion by casein micelles (Downey and Murphy 1975) and by (3) the possible presence in milk of inhibitors of lipolysis (Deeth and Fitz-Gerald 1975). The presence in milk of activators and their relative concentration may also determine whether milk will be spontaneously rancid or not (Jellema 1975 Driessen and Stadhouders 1974A Murphy et al. 1979 Anderson 1979). 

Lockene, A., Skottova, N., Olivecrona, G. Interactions of Lipoprotein Lipase with the Active-Site Inhibitor Tetrahydrolipstatin (Orlistat). Eur. J. Biochem. 1994, 222, 395 103. 

Thirdly, the lipoprotein lipase from Psuedomonos species (PSL) reacted with racemic cyanohydrin 45 to give the acetate (ethanoate) 46 of S configuration with 98% ee after 59% conversion (Scheme 3.4). The unreacted alcohol, effectively now resolved into the enantiomer of R configuration 47, because of its rejection by the enzyme, was then converted into the hydroxy ester 48, which is an important intermediate in the synthesis of an angiotensin-converting enzyme inhibitor (see Wang et alP). 

Lookene, A., Skottova, N. and Olive-crona, G. (1994) Interactions of lipoprotein lipase with the active-site inhibitor... 

In particular, LIF appears to be identical with HSF-III (hepatocyte-stimulating factor III), which is known to stimulate the synthesis of acute phase plasma proteins (Baumann and Wong, 1989), and with MLPLI (melanoma-derived lipoprotein lipase-inhibitor) which is produced in a human melanoma cell line, SEKI. LIF inhibits lipoprotein lipase activity in adipocytes and possibly causes cachexia (Mori et al., 1989). 

The principal lipase in bovine milk is a lipoprotein lipase (LPL Chapter 8) which is associated predominantly with the casein micelles and is isolated from its substrate, milk fat, by the MFGM, i.e. the enzyme and its substrate are compartmentalized. However, even slight damage to the membrane permits contact between enzyme and substrate, resulting in hydrolytic rancidity. The enzyme is optimally active at around 37°C and pH 8.5 and is stimulated by divalent cations, e.g. Ca (Ca complex free fatty acids, which are strongly inhibitory). The initial turnover of milk LPL is c. 3000 s i.e. 3000 fatty acid molecules are liberated per second per mole of enzyme (milk usually contains 1-2 mg lipase 1 , i.e. 10-20 nM) which, if fully active, is sufficient to induce rancidity in about 10 s. This never happens in milk due to a variety of factors, e.g. the pH, ionic strength and, usually, the temperature are not optimal the lipase is bound to the casein micelles the substrate is not readily available milk probably contains lipase inhibitors, including caseins. The activity of lipase in milk is not correlated with its concentration due to the various inhibitory and adverse factors. 

Decreases in plasma VLDL primarily result from the ability of these compounds to stimulate the activity of lipoprotein lipase, the enzyme responsible for removing triglycerides from plasma VLDL (Fig. 30.5). Additionally, fibrates can lower VLDL levels through PPARa-mediated stimulation of fatty acid oxidation, inhibition of triglyceride synthesis, and reduced expression of apoC-lll. This latter effect enhances the action of lipoprotein lipase, because apoC-lll normally serves as an inhibitor of this enzyme. Favorable effects on FIDL levels appear to be related to increased transcription of apoA-l and apoA-ll as well as a decreased activity of cholesteryl ester transfer protein. 

Yoshida, K., Shimizugawa, T., Ono, M., and Fumkawa, H. 2002. Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J. Lipid Res. 43, 1770-1772. 

Apoprotein II 16 OOO(dimer) Mainly VLDL and LDL Lipoprotein lipase inhibitor (Ki, 40mg/l) ApoC... 

Study of heparin binding to thrombin, 56 low-density lipoproteins, lipoprotein lipase, circulatory serine proteases, proteinase inhibitors, heparin-binding growth factors, blood vessel-associated proteins (fibronectin and laminin) and binding to cells and tissues. Study of anticoagulant activity and the modulation of the structure, function and metabolism of many proteins and en-2ymes. 

Possible physiological inhibitors of plasma lipoprotein lipase have been reported in plasma (Hollett and Meng, 1957), platelets (Hollett and Nestel, 1960), and white blood cells (Fekete et al., 1958). Their exact functional role remains to be established. Inhibition of plasma lipoprotein lipase activity has also been reported in pathological conditions, such as experimental pancreatitis (Kessler et al., 1962), clinical pancreatitis (Kessler et al., 1963), and idiopathic hyperlipemia (Klein and Lever, 1957). Several agents have been found to inhibit plasma lipoprotein lipase activity protamine and toluidine blue (Brown, 1952 Bragdon and Havel, 1954), Triton WR-1339 (Schotz et al., 1957), Triton A-20 and Tween 80 (Kellner et al., 1951), pituitary extracts (Rudman and Seid-... 

Park, Y., M.W. Pariza. Lipoxygenase Inhibitors Inhibit Heparin-Releasable Lipoprotein Lipase Activity in 3T3-L1 Adipocytes and Enhance Body Eat Reduction in Mice by Conjugated Linoleic Acid. Biochim. Biophys. Acta 1534 27—33 (2001). 

The nutritional conditions inducing activity of the lipoprotein lipase released by the tissue coincide with those increasing triglyceride uptake (Bragdon and Gordon 1958 Havel, Felts and van Duyne 1962 Bezman, Felts and Havel 1962). However, this correlation is far from complete. Poisons which are effective lipoprotein lipase inhibitors did not interfere with the uptake of triglycerides, while others which have no effect on the enzyme caused substantial reduction of uptake (Markscheid and Shaerir 1963). 

A lipoprotein lipase inhibitor was found in the serum of hyperlipemic subjects (Klein et al. 1959). The resistance of very low density lipoproteins (1.5X 10 Crmin.) to lipolysis, may also contribute to underutilization (Angerwall et al. 1962). In contrast to adipose tissue, triglyceride uptake by rat liver apparently does not require lipolysis (Olivecrona and Belfrage 1965). Variations between tissues, and species variations mentioned previously, complicate the interpretation of lipolysis data. 

Markscheid, L., and E. Shafrir Assimilation of lipoprotein triglyceride (TG) in vitro Comparison of various adipose tissues and lipoproteins and effect of lipoprotein lipase (LL) inhibitors. Israel J. Chem. 1, 205—207 (1963). 

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