Endothelial lipases

Endorphins Endosome Endothelial Cells Endothelial Lipase (EL)... 

Paradis E., Clavel S., Julien P., Murthy M. R. V., de Bilbao F., Arsenijevic D., Giannakopoulos P., Vallet P., and Richard D. (2004). Lipoprotein lipase and endothelial lipase expression in mouse brain regional distribution and selective induction following kainic acid-induced lesion and focal cerebral ischemia. Neurobiol. Dis. 15 312-325. 

K35. Kuusi, T., Kinnunen, P. K., and Nikkila, E. A., Hepatic endothelial lipase antiserum influences rat plasma low and high density lipoproteins in vivo. FEBS Lett. 104,384-388 (1979). 

The area of HDL cholesterol metabolism and function holds considerable promise in atheroprotection. Novel HDL-directed therapeutic interventions mainly target LXR (liver X receptor), ABCA1, apoA-I, CEPT (cholesteryl ester transfer protein), and EL (endothelial lipase) [12, 16, 70], The contribution of pharmacogenomics in the development of such drugs has not only been proven to be important (Fig. 2) but been required by the international drug regulatory bodies. Representative examples are presented below. 

Ishida T, Choi S, Knndu RK, Hirata K, Rubin EM, Cooper AD, Quertermous T (2003) Endothelial lipase is a major determinant of HDL level. J Clin Invest 111 347-355... 

Brown RJ, Lagor WR, Sankaranaravanan S, Yasuda T, Quertermous T, Rothblat GH, Rader DJ (2010) Impact of combined deficiency of hepatic lipase and endothelial lipase on the metabolism of both high-den-sity lipoproteins and apolipoprotein B-containing lipoproteins. Circ Res 107 357-364... 

W. Jin, S. John, U. Broedl, J.M. Glick, and D.J. Rader, Inhibition of endothelial lipase causes increased HDL cholesterol levels in vivo, J. Clin. Invest., 2003, 111, 357-362. 

Endothelial Lipase A Novel Drug Target for HDL and Atherosclerosis ... 

Fig. 8.1 A model of endothelial lipase was created using the reported amino acid sequence [3]. The structure was based on the...

Fig. 8.2 Endothelial lipase (EL) is a member of the triglyceride lipase gene family. It more closely resembles lipoprotein lipase (LPL) and hepatic lipase (HL) and is predicted to have arisen from a common precursor.

Enzymatic Activity and Effects on Cellular Lipid Metabolism of Endothelial Lipase... 

Hirata et al. [4] have noted that activated endothelial cells had increased endothelial lipase mRNA. Jaye et al. found that, upon stimulation with phorbol ester, the intensity of both 68 and 40 kDa bands increased in HCAEC and new bands of approximately 55 kDa, 38 and 36 kDa appeared in both HCAEC and HUVEC upon stimulation [3]. These new bands were not characterized, but may represent alternative splice products or an enzymatic cleavage product. Hirata et al. demonstrated that the expression of endothelial lipase is regulated by cytokines, by fluid shear stress and by cyclic stretch [18]. Using both HUVEC and HCAEC, they examined the effects of IL-1/ and TNF-a on endofhelial hpase mRNA levels. Exposure to IL-1/ for 24 h resulted in a 6.5-fold increase in EL mRNA in both HUVEC and HCAEC. TNF-a produced a ca. 4-fold increase in EL mRNA. The same group examined the response of both HUVEC and HCAEC to shear stress, and found a 2-3-fold increase in EL mRNA after 6 h of exposure. Additionally, cyclic stretch resulted in a 2.7-fold increase in EL mRNA. They concluded fhat EL expression is highly regulated by factors implicated in fhe development of vascular disease. 

The cytokine-induced increase in endofhelial lipase expression and secretion by endofhehal ceUs is in marked contrast to fhe effect of cytokines on hepatic hpase and Upoprotein hpase expression. Feingold et al. found that cytokines down-regu-late Upoprotein hpase [19] and hepatic lipase [20] expression. Both acute and chronic inflammatory conditions are associated with decreased HDL levels [21]. A decrease in HL levels in inflammatory states would be expected to increase HDL levels. These results support fhe possibihty fhat endothelial lipase has a significant role in regulating HDL levels, especiaUy in inflammatory states. 

Fig. 8.9 Current working model of endothelial lipase function. EL is synthesized by endothelial cells in variety of various tissues, is secreted and binds to HSPGs on the cell surface. There it binds to circulating lipoproteins, hydrolyzing phospholipids and resulting in lipoprotein particles that are reduced in phos-...

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