Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Ma, Ke; Çilingiroğlu, Mehmet; Otvos, James D.; Ballantyne, Christie M.; Marian, Ali J.; Chan, Lawrence

doi:10.1073/pnas.0438039100

Cited by 216 publications

(251 citation statements)

References 34 publications

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“…3G), which may in part account for the increased HDL in SHP mutants. 31 The expressions for hormone-sensitive lipase were undetectable in lean SHP ϩ/ϩ and SHP Ϫ/Ϫ livers, but were elevated in obese OB Ϫ/Ϫ and OB Ϫ/Ϫ /SHP Ϫ/Ϫ mice (Fig. 3H).…”

Section: Shp Deficiency Alters Brown Fat Function But Notmentioning

confidence: 99%

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

et al. 2007

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The orphan receptor Small Heterodimer Partner (SHP, NROB2) regulates metabolic pathways, including hepatic bile acid, lipid, and glucose homeostasis. We reported that SHP-deletion in leptin-deficient OB ؊/؊ mice increases insulin sensitivity, and prevents the development of fatty liver. The prevention of steatosis in OB ؊/؊ /SHP ؊/؊ double mutants is not due to decreased body weight but is associated with increased hepatic very-low-density lipoprotein (

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Section: Shp Deficiency Alters Brown Fat Function But Notmentioning

confidence: 99%

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

et al. 2007

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“…The primary action of CETP is to mediate the transfer of cholesteryl esters from HDL to VLDL and LDL in exchange for triglyceride (Figure 2). [27][28][29][30] CETP also promotes the transformation of HDL 2 to HDL 3 , an action that could promote reverse cholesterol transport. CETP inhibition, on the other hand, results in an increase in HDL by markedly delaying catabolism of apoA-I and A-II.…”

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Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

2005

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Abstract-Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol.Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by Ͼ50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective. Key Words: atherosclerosis Ⅲ cholesterol Ⅲ lipids Ⅲ metabolism Ⅲ statins A lthough lipid-lowering therapies now have the capability of reducing LDL cholesterol to levels recommended by the National Cholesterol Education Program (NCEP) guidelines in as many as 90% of treated patients, 1 the rate of cardiovascular events is reduced by only 20% to 35% in large, randomized trials. These data suggest that the LDL target set by NCEP guidelines may be too high. 1-5 Indeed, among patients with acute myocardial infarction, Ϸ15% have LDL levels Ͻ100 mg/dL on presentation.A complementary hypothesis is that there is a finite limit to the benefit of LDL lowering and that other non-LDL lipid risk factors must be managed for optimal outcomes. Indeed, epidemiological studies suggest that low HDL cholesterol may be a risk factor comparable in importance to high LDL and that the 2 risk factors are independent (Figure 1). 6,7 Although the mechanism by which HDL reduces the development of atherosclerosis has not been defined with certainty, acceleration of reverse cholesterol transport, antioxidant activity, and antiinflammatory action are likely to play central roles. 8 -10 In contrast to the ability of potent statins to reduce the level of LDL by Ͼ50%, however, no currently approved therapy increases HDL by a comparable magnitude. The most potent, currently available HDL-raising therapy is nicotinic acid. This therapy also has a multitude of other antiatherosclerotic effects on the levels of LDL and triglycerides, lipid oxidation, and endothelial function. 11 Combination therapy with a statin has been reported to increase HDL levels by Ϸ30% 12 and to decrease cardiac events...

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“…Al inyectar el AdhEL a un ratón transgénico para Apo A-I (que tiene niveles plasmáticos muy altos de c-HDL y apo A-1), también se obtuvo una reducción del c-HDL y de apo A-I 2 . Un estudio realizado en ratones transgénicos que sobreexpresan la enzima (LE +/+ ) reportó una disminución de 19% en los niveles de c-HDL, mientras que en ratones defi cientes en LE (LE -/-) se encontró un aumento de 25-57% en los del mismo 10 , apoAI y apoE 11 . Otro estudio que utilizó un anticuerpo antiLE en ratones, observó un aumento de 25-60% en los niveles de c-HDL 12 .…”

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“…En humanos, se han identifi cado variantes genéticas de LE en personas con c-HDL elevado 11,13,14,15 . En un estudio de 372 personas portadoras de un polimorfi smo que determina la reducción de la actividad enzimática, se encontró que los homocigotos para esta mutación tienen un colesterol HDL 14% mayor que aquellos sujetos que no presentaron la mutación o que resultaron heterocigotos para la misma 11 .…”

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“…En un estudio de 372 personas portadoras de un polimorfi smo que determina la reducción de la actividad enzimática, se encontró que los homocigotos para esta mutación tienen un colesterol HDL 14% mayor que aquellos sujetos que no presentaron la mutación o que resultaron heterocigotos para la misma 11 . Otro estudio realizado en niños sanos en edad escolar, mostró que la presencia de distintos polimorfi smos en el gen de LE se asocia a variaciones en los niveles plasmáti-cos de c-HDL, lo que sugiere que las alteraciones genéticas de esta enzima podrían ser una de las determinantes en las variaciones del c-HDL 14 .…”

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Lipasa endotelial y su relación con la enfermedad cardiovascular y diabetes mellitus tipo 2

2012

Rev. méd. Chile

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Endothelial lipase (EL) is synthetized by endothelial cells and its mainL as lipasas son un conjunto de enzimas hidrosolubles que hidrolizan sustratos como los triglicéridos y fosfolípidos, tienen una estructura similar y son fundamentales en el metabolismo de las lipoproteínas y los lípidos. Esta familia está compuesto por la la lipasa pancreática, la lipasa hepática (LH) y la lipasa lipoproteica (LPL) 1 .En el año 1999 dos grupos describieron, en forma simultánea, un cuarto miembro de esta familia, la lipasa endotelial (LE). Esta nueva enzima se ha relacionado con el proceso de aterogénesis, principalmente por su participación en la modulación de las concentraciones plasmática de colesterol HDL (c-HDL) 2,3 .LPL y LH son los miembros de la familia de las lipasas mejor caracterizados en la literatura. LPL es sintetizada principalmente por adipocitos, células de músculo esquelético y micardio, mientras que LH es sintetizada por los hepatocitos. Tanto LPL como LH participan en la regulación de los niveles plasmáticos de colesterol y triglicéridos. LPL actúa principalmente sobre triglicéridos hidrolizando lipoproteínas ricas en triglicéridos, mientras que LH tiene actividad sobre triglicéridos y fosfolopidos, hidrolizando LDL y HDL, principalmente las pequeñas con mayor contenido de triglicéridos.Lipasa endotelial: estructura y síntesis LE es una enzima de 482 aminoácidos que se identifi có inicialmente en cultivo de células endoteliales de cordón umbilical humano (HUVEC) y en líneas celulares de macrófagos humanos THP-1 expuestos a LDL oxidadas 2,3 .Esta enzima muestra una secuencia similar a LPL (44%) y LH (41%), conservando la secuencia inicial de la señal secretora y el residuo de cisteína implicado en la unión de puentes disulfuro necesarios para la actividad enzimática 4 . La principal diferencia estructural de LE con respecto a los otros miembros de la familia de las lipasas se encuentra

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Endothelial lipase is a major genetic determinant for high-density lipoprotein concentration, structure, and metabolism

Cited by 216 publications

References 34 publications

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition

Lipasa endotelial y su relación con la enfermedad cardiovascular y diabetes mellitus tipo 2

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