Low Hepatic Lipase Activity Is a Novel Risk Factor for Coronary Artery Disease

Dugi, Klaus A.; Brandauer, Karin; Schmidt, Nikolaus; Nau, Barbara; Schneider, Jochen G.; Mentz, Stefani; Keiper, Tanja; Schaefer, Juergen R.; Meißner, Christoph; Kather, H; Bahner, M. L.; Fiehn, W.; Kreuzer, Joerg

doi:10.1161/hc5001.100795

Cited by 86 publications

(54 citation statements)

References 43 publications

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“…Numerous reports indicate that HL can have either pro-atherogenic or anti-atherogenic activities in humans and mice, depending on the details of the system undergoing study. 30,31,32 For example, alterations in HL expression result in strikingly different effects in apoE KO and LDLR KO mice, despite the similarities in morphology of their aortic atherosclerotic lesions. HL deficiency dramatically reduces aortic root atherosclerosis in apoE knockout mice 19 via poorly understood mechanisms that likely include alterations in lipoprotein metabolism, indicating a pro-atherogenic role for HL.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the influence of HL on murine atherosclerosis of this sort has not be defined previously; however, examination of HL effects on coronary arterial atherosclerosis in humans has been reported. 30 The diverse effects of HL on atherosclerosis in different systems is not surprising, because HL is a complex protein that exhibits distinct lipolytic 16 and ligand-binding 13-15,38 -41 activities that have multiple effects on lipoprotein composition and metabolism, and thus could influence atherogenesis via a variety of mechanisms. 29,33 For example, in apoE KO mice, HL deficiency may be anti-atherogenic because it raises HDL cholesterol, increases the capacity of HDL to promote cellular cholesterol efflux in vitro, 19 prevents HL-mediated increases in the atherogenicity of very-low-density lipoprotein particles, 19,34,35 increases plasma apoA-I and apoA-IV levels, 19,20 or alters the phospholipid composition of lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…20 There are also studies showing that HL can be anti-atherogenic. 30,33 Thus, whereas HL modulates atherosclerosis, its precise effects vary depending on the system under study.Here, we examined the role of atherosclerosis in CHD in dKO mice by examining the effects of HL deficiency. We found that HL deficiency significantly reduced aortic root and occlusive coronary arterial atherosclerosis, delayed the onset and/or progression of CHD, and increased longevity (37%).…”

mentioning

confidence: 99%

“…20 There are also studies showing that HL can be anti-atherogenic. 30,33 Thus, whereas HL modulates atherosclerosis, its precise effects vary depending on the system under study.…”

mentioning

confidence: 99%

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Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

Karackattu

Trigatti

Krieger

2006

ATVB

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Objective-SR-BI/apolipoprotein (apo) E double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the effects on this pathology of hepatic lipase (HL) deficiency, which has been shown to significantly modulate atherosclerosis. Method and Results-The SR-BI/apoE/HL triple knockout (tKO) mice generated for this study lived significantly longer (37%) than corresponding dKO controls (average lifespans: 63.0Ϯ0.8 versus 46.0Ϯ0.3 days), despite their increased plasma cholesterol levels. At 6 weeks of age, compared with dKO mice, tKOs exhibited significantly less aortic root and coronary artery occlusive atherosclerosis, and improved cardiac structure and function. However, by 9 weeks of age the hearts of tKO mice exhibited lipid-rich coronary occlusions, myocardial infarctions, and cardiac dysfunction essentially identical to that of 6-week-old dKO mice. Conclusions-HL-deficiency delays the onset and/or progression of atherosclerosis via a SR-BI-independent mechanism.Extent of occlusive coronary arterial lesions was more closely associated with cardiac dysfunction and lifespan than the amount of aortic root atherosclerosis, suggesting that these occlusions in dKO mice are responsible for ischemia, myocardial infarctions, and premature death. Key Words: atherosclerosis Ⅲ hepatic lipase Ⅲ high density lipoprotein receptor Ⅲ myocardial infarction T hough apolipoprotein E (apoE) or low-density lipoprotein receptor (LDLR) knockout (KO) murine models of dyslipidemia are often used to study lipoprotein metabolism and atherosclerosis, 1 they usually do not exhibit spontaneous occlusive coronary artery disease, myocardial infarction (MI), cardiac dysfunction and premature death, hallmarks of human coronary heart disease (CHD). Double knockout (dKO) mice deficient in the high-density lipoprotein (HDL) receptor (scavenger receptor class B type I, SR-BI) and apoE exhibit extensive aortic sinus atherosclerosis (advanced plaques with fibrous caps 2 that contain macrophages [unpublished data, 2005]), occlusive coronary arterial atherosclerosis (cellular and acellular plaques containing lipid [including cholesterol clefts], collagen, and fibrin deposits 3 ), and acute CHD when young (4 to 6 weeks old). 2-4 At 6 weeks of age, dKO hearts exhibit multiple, large infarctions with extensive fibrosis around the ventricular outflow tract and patchy MIs in the apex, right ventricular wall and interventricular septum. 3 In addition, they are hypertrophic with LV dilation, and exhibit severe dysfunction, including multiple electrocardiographic (ECG) abnormalities (ST elevation and depression, anesthesia induced conductance abnormalities (eg, bradyarrhythmias, AV blocks)), a 70% reduction in ϮdP/dT, and 50% reduced ejection fraction. The dKO mice die between 5 and 8 weeks of age (mean 6 weeks). 2,3 Similarities between dKO and human CHD raised the possibility that these mice may help to ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…20 There are also studies showing that HL can be anti-atherogenic. 30,33 Thus, whereas HL modulates atherosclerosis, its precise effects vary depending on the system under study.…”

mentioning

confidence: 99%

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Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

Karackattu

Trigatti

Krieger

2006

ATVB

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“…Indeed, human and animal studies support both proatherogenic and anti-atherogenic roles for HL (14,(31)(32)(33). In humans, low or absent HL activity has been associated with increased risk of coronary artery disease (31,34,35). Other studies have concluded that decreased HL activity does not influence susceptibility to coronary artery disease (8).…”

mentioning

confidence: 99%

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

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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...

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The cross‐sectional study of hepatic lipase SNPs and plasma lipid levels

Wang

Luo

et al. 2020

Food Science & Nutrition

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By the combination of meta‐analysis, the data of the 1,000 Genomes Project Phase 3, and the promoter sequence of hepatic lipase (LIPC), we performed the cross‐sectional study to explore the associations of four variants (rs1077835; rs1077834; rs1800588 [C‐514T], and rs2070895 [G‐250A]) in LIPC promoter with plasma lipid levels. Our results indicate that the first and the next three of the four SNPs are, respectively, reported to be associated with the decreased and increased HDL‐c level. Meta‐analysis of 87 studies with 101,988 participants indicates that HDL‐c level in rs1800588 (C‐514T) (pooled mean difference = 0.03, 95%CI (0.03, 0.04), p < .001) and rs2070895 (G‐250A) (pooled mean difference = 0.07, 95%CI (0.05, 0.09), p < .001) is higher in allele T or A carriers. Similarly, LDL‐c, TC, TG, and BMI levels are generally increased in T or A alleles carriers. We failed to conduct the meta‐analysis of rs1077835 and rs1077834 due to the limited previous reports. Data from the 1,000 Genomes indicate that the allele frequencies of the four SNPs in total or subpopulations are almost equal to each other. The paired value r2 and D' of the four SNPs are larger than 0.8, which indicate the linkage disequilibrium of the four variants. The analysis of LIPC promoter indicate that C‐514T and G‐250A are, respectively, located in transcriptional factor binding sites of USF1and Pbx1b, which may partly explain the effect of the two SNPs on the decreased LIPC activity in the alleles carriers and the corresponding increased plasma lipids hydrolyzed by LIPC. These results may help us to better understand the different effects of the four SNPs on the plasma lipid levels among subpopulations and offer clues for future clinical treatment of dyslipidemia‐related diseases.

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Low Hepatic Lipase Activity Is a Novel Risk Factor for Coronary Artery Disease

Cited by 86 publications

References 43 publications

Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

Hepatic Lipase Deficiency Delays Atherosclerosis, Myocardial Infarction, and Cardiac Dysfunction and Extends Lifespan in SR-BI/Apolipoprotein E Double Knockout Mice

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

The cross‐sectional study of hepatic lipase SNPs and plasma lipid levels

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