Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice

Zhao, Bin; Song, Jingmei; Chow, Woon N.; Clair, Richard W. St.; Rudel, Lawrence L.; Ghosh, Shobha

doi:10.1172/jci30485

Cited by 109 publications

(127 citation statements)

References 46 publications

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“…In nCEH transgenic mice crossed into an Ldlr-null background, highfat/cholesterol diet-induced atherosclerosis was significantly reduced because cholesterol efflux and reverse cholesterol transport (RCT) were enhanced, resulting in increased elimination of cholesterol from the body as bile acids in the feces (Zhao et al, 2007). These results demonstrate that macrophage-specific overexpression of nCEH is antiatherogenic and that this protein is potentially a novel target for the treatment of atherosclerosis.…”

Section: Hydrolysis Of Cholesterol Estersmentioning

confidence: 99%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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Section: Hydrolysis Of Cholesterol Estersmentioning

confidence: 99%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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“…Recently, Ghosh et al (18) reported cloning of cholesteryl ester hydrolase (CEH) which mediates the hydrolysis of CE in human monocyte-derived macrophages. They have further shown that macrophage-specific transgenic expression of CEH significantly reduced atherosclerosis in low density lipoprotein receptor knock-out mice (19). However, the CEH gene is identical to the human orthologue of TGH, which was originally reported as a microsomal TG lipase in rat liver by Lehner et al (20).…”

mentioning

confidence: 97%

Identification of Neutral Cholesterol Ester Hydrolase, a Key Enzyme Removing Cholesterol from Macrophages

Okazaki

Igarashi

Nishi

et al. 2008

Journal of Biological Chemistry

109

127

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Unstable lipid-rich plaques in atherosclerosis are characterized by the accumulation of macrophage foam cells loaded with cholesterol ester (CE). Although hormone-sensitive lipase and cholesteryl ester hydrolase (CEH) have been proposed to mediate the hydrolysis of CE in macrophages, circumstantial evidence suggests the presence of other enzymes with neutral cholesterol ester hydrolase (nCEH) activity. Here we show that the murine orthologue of KIAA1363, designated as neutral cholesterol ester hydrolase (NCEH), is a microsomal nCEH with high expression in murine and human macrophages. The effect of various concentrations of NaCl on its nCEH activity resembles that on endogenous nCEH activity of macrophages. RNA silencing of NCEH decreases nCEH activity at least by 50%; conversely, its overexpression inhibits the CE formation in macrophages. Immunohistochemistry reveals that NCEH is expressed in macrophage foam cells in atherosclerotic lesions. These data indicate that NCEH is responsible for a major part of nCEH activity in macrophages and may be a potential therapeutic target for the prevention of atherosclerosis.Atherosclerotic cardiovascular diseases are the leading causes of mortality in industrialized countries, despite advances in the management of coronary risk factors. Heart attacks arise from thrombotic occlusion of coronary arteries following the rupture of plaques. Lipid-rich plaques, which are characterized by a plethora of CE 3 -laden macrophage foam cells, are prone to rupture (1). Thus, it is important to clarify the mechanism that eliminates CE from macrophage-derived foam cells. Foam cells are generated by the unlimited uptake of modified lipoproteins through scavenger receptors (2). Cholesterol in the lipoproteins is stored in lipid droplets as CE after re-esterification by acyl-CoA:cholesterol acyltransferase 1 (ACAT1) (3). Hydrolysis of CE is the initial step toward elimination of cholesterol from foam cells (4). Free cholesterol thus generated is re-esterified or is released from the cells primarily through ATP-binding cassette transporters (5). Thus, the balance between synthesis and hydrolysis of CE conceivably governs the level of CE in macrophages.Hydrolysis of CE in macrophages has been known for over 40 years (6). However, its molecular mechanism has yet to be fully understood. Circumstantial evidence suggests that the hydrolysis of CE in foam cell macrophages is mediated by hormonesensitive lipase (HSL), a multifunctional enzyme that catalyzes the hydrolysis of triacylglyerol (TG), diacylglycerol, CE, and retinyl ester in various organs such as adipose tissue, muscle, and testis (7,8). This belief is supported by the following facts. First, it has been demonstrated that various lines of macrophages express HSL (9 -12). Second, HSL expression is regulated coordinately with nCEH activity in murine macrophages (13). Third, we (14) and others (15) demonstrated that overexpression of HSL is associated with increased hydrolysis of CE stores in THP-1 and RAW264.7 macrophages.However, recent ...

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“…Radioactivity associated with plasma and liver was monitored. Biliary cholesterol as well as bile acids were extracted from the gall bladder bile and associated radioactivity was determined as described (16).…”

Section: Flux Of Hdl-[ 3 H]ce To Bile In Vivomentioning

confidence: 99%

“…Separated lipids were identified by staining with iodine, marked, and silica-gel scraped to determine the associated radioactivity. Gallbladder bile was used to extract biliary bile acids and cholesterol as described (16). Biliary phospholipids were determined by using the Phospholipids C kit from Wako (Richmond, VA).…”

Section: Analytical Proceduresmentioning

confidence: 99%

Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

Wang

Bie

Ghosh

2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org cholesterol homeostasis in mammals, including humans. Liver is the central organ for regulating the rate of cholesterol biosynthesis as well as coordinating the elimination of cholesterol via direct secretion into bile or by conversion to more water soluble bile acids. While dietary cholesterol fluxes through the liver in the form of chylomicron remnants taken up via the VLDL or LDL receptor, endogenously synthesized cholesterol is secreted by the liver as part of VLDL and returns to the liver either as IDL or LDL. However, excess cholesterol from nonhepatic peripheral tissues, including artery wall-associated macrophage foam cells, returns to the liver as part of HDL where about 80% of cholesterol is present as cholesteryl esters (CEs) and unesterified or free cholesterol (FC) represents less than 20% of the total HDL cholesterol. HDL-FC is thought to be rapidly and directly secreted into bile without entering the hepatic FC pools (1, 2) and the fate of HDL-associated CEs (HDL-CEs) within a hepatocyte is now beginning to be defined. We identified the neutral CE hydrolase (CEH; gene symbol CES1 in humans and Ces1d in mice) as the enzyme facilitating the intrahepatic hydrolysis of HDL-CE (3) and demonstrated the requirement of SR-BI for this process (3, 4). Gain-of-function (5) and loss-of-function (6) studies further established the role of hepatic CEH in regulating the flux of HDL-CEs to bile, preferentially as bile acids.HDL-derived cholesterol (FC or FC generated after CEH-mediated hydrolysis of HDL-CE) can potentially have multiple fates within the hepatocyte. It can either be resecreted as part of nascent HDL or VLDL following esterification; the two processes that will not facilitate the final elimination of cholesterol from the body. Alternatively, FC can either be directly secreted into bile or converted into bile acids prior to biliary secretion; the two pathways resulting in final elimination of cholesterol from the body. While selective uptake of HDL-CE/FC occurs via SR-BI at the Abstract While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 Due to the lack of enzymes required to degrade the steroid nucleus, balance between synthesis and elimination of cholesterol is crucial to the maintenance of whole body

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Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice

Cited by 109 publications

References 46 publications

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Identification of Neutral Cholesterol Ester Hydrolase, a Key Enzyme Removing Cholesterol from Macrophages

Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

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