Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Zhang, Nong; González-Navarro, Herminia; Amar, Marcelo; Freeman, Lita A.; Knapper, Catherine L.; Neufeld, Edward B.; Paigen, Beverly; Hoyt, Robert F.; Fruchart‐Najib, Jamila; Santamarina-Fojo, Silvia

doi:10.1172/jci16484

Cited by 30 publications

(47 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Analysis of Plasma, Lipid Lipoproteins, and Apolipoproteins-After a 4-h fast, mouse plasma samples were collected from blood obtained from the retro-orbital plexus of mice anesthetized with methoxyflurane (Pitman-Moore, Mundelein, IL) and placed into precooled tubes containing EDTA as reported (45). Total cholesterol (TC), TG, PL, and free cholesterol (FC) in plasma samples were analyzed using enzyme kits (Sigma, St. Louis, MO) as described (45).…”

Section: Methodsmentioning

confidence: 99%

“…Total cholesterol (TC), TG, PL, and free cholesterol (FC) in plasma samples were analyzed using enzyme kits (Sigma, St. Louis, MO) as described (45). HDL-C was determined as the cholesterol remaining after precipitation of apoB-Lp with dextran sulfate (Bayer Corp., Tarrytown, NY) as described (28).…”

Section: Methodsmentioning

confidence: 99%

“…Non-HDL-C was obtained by subtraction of the HDL-C from the TC. Plasma apolipoprotein levels from four to six control and transgenic mice were analyzed by sandwich enzyme-linked immunosorbent assay using polyclonal antibodies against synthetic peptides of mouse apoA-I and apoB as described (45) and by 4 -12% SDS-PAGE (0.2-1 l of plasma). Separated plasma lipoproteins were transferred to an Immobilon membrane.…”

Section: Methodsmentioning

confidence: 99%

“…For FPLC plasma lipoprotein analysis, 100 l of pooled mouse plasma (n ϭ 5) were separated by gel filtration using two Superose 6 HR 10/30 columns (Amersham Biosciences) connected in series (45). Lipids in the recovered fractions were analyzed using enzyme kits as described (25,28).…”

Section: Methodsmentioning

confidence: 99%

“…Finally, HL deficiency in E-KO and lecithin:cholesterol acyltransferase-overexpressing transgenic mice significantly reduces aortic atherosclerosis despite the increase in cholesterol content in apoB-Lp (44,45). These conflicting data in mice have been explained in part by the recent discovery of HL expression in mouse macrophages (46) and by bone marrow transplantation studies demonstrating that macrophage HL expression in the arterial wall enhances early lesion formation in E-KO and lecithin:cholesterol acyltransferase-overexpressing transgenic mice, without modification of plasma lipoprotein lipids or HL activities (45). Despite these recent advances, the independent roles of the ligandbinding versus lipolytic function in lipoprotein metabolism and the development of atherosclerosis are not well defined.…”

mentioning

confidence: 94%

See 4 more Smart Citations

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

González-Navarro

Zhang

Amar

et al. 2004

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

To investigate the separate contributions of the lipolytic versus ligand-binding function of hepatic lipase (HL) to plasma lipoprotein metabolism and atherosclerosis, we compared mice expressing catalytically active wild-type HL (HL-WT) and inactive HL (HL-S145G) with no endogenous expression of mouse apoE or HL (E-KO ؋ HL-KO, where KO is knockout). HL-WT and HL-S145G reduced plasma cholesterol (by 40 and 57%, respectively), non-high density lipoprotein cholesterol (by 48 and 61%, respectively), and apoB (by 36 and 44%, respectively) (p < 0.01), but only HL-WT decreased high density lipoprotein cholesterol (by 67%) and apoA-I (by 54%). Compared with E-KO ؋ HL-KO mice, both active and inactive HL lowered the pro-atherogenic lipoproteins by enhancing the catabolism of autologous 125 I-apoB very low density/intermediate density lipoprotein (VLDL/ IDL) (fractional catabolic rates of 2.87 ؎ 0.04/day for E-KO ؋ HL-KO, 3.77 ؎ 0.03/day for E-KO ؋ HL-WT, and 3.63 ؎ 0.09/day for E-KO ؋ HL-S145G mice) and 125 IapoB-48 low density lipoprotein (LDL) (fractional catabolic rates of 5.67 ؎ 0.34/day for E-KO ؋ HL-KO, 18.88 ؎ 1.72/day for E-KO ؋ HL-WT, and 9.01 ؎ 0.14/day for E-KO ؋ HL-S145G mice). In contrast, the catabolism of apoE-free, 131 I-apoB-100 LDL was not increased by either HL-WT or HL-S145G. Infusion of the receptor-associated protein (RAP), which blocks LDL receptor-related protein function, decreased plasma clearance and hepatic uptake of 131 I-apoB-48 LDL induced by HL-S145G. Despite their similar effects on lowering proatherogenic apoB-containing lipoproteins, HL-WT enhanced atherosclerosis by up to 50%, whereas HL-S145G markedly reduced aortic atherosclerosis by up to 96% (p < 0.02) in both male and female E-KO ؋ HL-KO mice. These data identify a major receptor pathway (LDL receptor-related protein) by which the ligand-binding function of HL alters remnant lipoprotein uptake in vivo and delineate the separate contributions of the lipolytic versus ligand-binding function of HL to plasma lipoprotein size and metabolism, identifying an anti-atherogenic role of the ligand-binding function of HL in vivo.Hepatic lipase (HL) 1 is a 64-kDa lipolytic enzyme that plays a major role in lipoprotein metabolism. It is synthesized and secreted primarily by hepatocytes (1, 2) and is anchored to the vascular endothelium via heparin sulfate proteoglycans. HL functions both as an acylglycerol hydrolase and a phospholipase, hydrolyzing triglycerides (TG) and phospholipids (PL) in chylomicron remnants and intermediate density lipoproteins (IDL). In humans, HL plays a major role in determining low density lipoprotein (LDL) subclass distribution, which may in turn modulate atherogenic risk (3-7). HL is also an important determinant of high density lipoprotein (HDL) concentration and subclass distribution, converting the phospholipid-rich HDL 2 to HDL 3 (3, 4, 8 -14).In addition to its function as a lipolytic enzyme, HL has a separate role in lipoprotein metabolism by directly facilitating the uptake of lipoproteins and lipoprotein lip...

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 94%

See 3 more Smart Citations

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

González-Navarro

Zhang

Amar

et al. 2004

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Atherosclerosis II : HDL Elevation

Ali

Hunt

Sinclair

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

Atherosclerosis is an arterial disease associated with elevated plasma lipid levels and is a major cause of morbidity and mortality worldwide. Clinical trials have demonstrated that reduction of low‐density lipoprotein cholesterol (LDL‐C), as can be accomplished with HMG‐CoA reductase inhibitors (statins), leads to a reduction in coronary events and mortality by about 25%. Conversely, epidemiological evidence indicates that high‐density lipoprotein cholesterol (HDL‐C) levels have an inverse correlation with risk of coronary artery disease. The beneficial effects of HDL have been attributed to its involvement in the movement of cholesterol from the periphery to the liver as well as to its apparent antioxidant and anti‐inflammatory activities. Consequently, there is much interest in identifying therapeutic approaches to raising HDL that will be useful as a treatment for atherosclerosis and dyslipidemias. The properties and physiologic role of HDL, as well as approaches to increasing plasma HDL concentrations, will be summarized.

show abstract

Hepatic lipase: Friend or foe and under what circumstances?

Jansen¹

2004

Curr Atheroscler Rep

View full text Add to dashboard Cite

Hepatic lipase (HL) plays a role in the metabolism of chylomicron and very low-density lipoprotein remnants, low-density lipoproteins (LDL), and high-density lipoproteins (HDL), which are all implicated in atherosclerosis. Considering the effects of HL on these lipoproteins, it appears that HL has pro- as well as antiatherogenic potential. In line with clinical observations, most effects of HL on lipoprotein metabolism during hypertriglyceridemia may be interpreted as promoting atherosclerosis (formation of small, dense LDL, lowering of HDL levels), whereas most effects during hypercholesterolemia seem to be potentially antiatherogenic (stimulation of reverse cholesterol transport, clearing of intermediate-density lipoprotein). The potential modulation of pro- or antiatherogenics effect of HL by other factors, such as LDL receptor, cholesterol ester transfer protein, lipoprotein lipase, and ATP-binding cassette A-1 activity, is discussed.

show abstract

Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice

Cited by 30 publications

References 59 publications

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

Atherosclerosis II : HDL Elevation

Hepatic lipase: Friend or foe and under what circumstances?

Contact Info

Product

Resources

About