Hepatic Lipase Deficiency Increases Plasma Cholesterol but Reduces Susceptibility to Atherosclerosis in Apolipoprotein E-deficient Mice

Mezdour, Hafid; Jones, Robert G.; Dengremont, Catherine; Castro, Graciela; Maeda, Nobuyo

doi:10.1074/jbc.272.21.13570

Cited by 111 publications

(97 citation statements)

References 34 publications

(37 reference statements)

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“…5). Consistent with previous reports showing a dissociation between the plasma levels of pro-atherogenic apoB-Lp and development of aortic atherosclerosis in E-KO ϫ HL-KO mice (44,45), aortic atherosclerosis was significantly increased in female E-KO ϫ HL-WT mice at 3 (3.5-fold, p Ͻ 0.001), 5 (9.2-fold, p Ͻ 0.0001), and 7 (2.5-fold, p Ͻ 0.0001) months of age. A trend toward an increased mean aortic lesion area was noted in male E-KO ϫ HL-WT mice at 3 and 5 months of age, which reached statistical significance at 7 months of age (2-fold, p Ͻ 0.04) compared with male E-KO ϫ HL-KO mice.…”

Section: Catalytically Inactive Hl-s145g Alters the Plasma Lipid Profsupporting

confidence: 93%

“…HL-WT markedly lowered the plasma concentrations of TC, TG, PL, CE, non-HDL-C, and apoB by up to 52% (p Ͻ 0.01) in E-KO mice, indicating that HL will partially but not completely correct the hyperlipidemic effect (44,58) induced by the absence of apoE in this mouse model. Similarly, even in the absence of lipolysis, catalytically inactive HL-S145G decreased the plasma levels of TC, TG, PL, CE, non-HDL-C, and apoB by up to 61% (p Ͻ 0.01).…”

Section: Figmentioning

confidence: 85%

“…Mice-Previous studies have shown that HL deficiency significantly raises the plasma TC, non-HDL-C, and apoB levels in E-KO mice (44,45,58). Consistently, compared with male and female E-KO ϫ HL-KO mice, male and female E-KO ϫ HL-WT mice that expressed fully active HL had reduced plasma levels of TC (by 40% (p Ͻ 0.01) and 42% (p Ͻ 0.0001), respectively), TG (by 27% (p ϭ 0.04) and 52% (p Ͻ 0.0001), respectively), PL (by 43 and 50% (p Ͻ 0.0002), respectively), cholesterol ester (CE; by 47% (p Ͻ 0.002) and 45% (p Ͻ 0.0001), respectively), HDL-C (by 67% (p Ͻ 0.0001) and 40% (p Ͻ 0.02), respectively), non-HDL-C (by 48% (p Ͻ 0.002) and 44% (p Ͻ 0.0001), respectively), apoB (by 36 and 35% (p Ͻ 0.0001), respectively), and apoA-I (by 54 and 46% (p Ͻ 0.0001), respectively) ( Fig.…”

Section: Catalytically Active Hl-wt and Inactive Hl-s145g Lower The Pmentioning

confidence: 99%

“…Atherosclerosis was also significantly reduced (p Ͻ 0.004) in E-KO ϫ HL-S145G mice compared with E-KO ϫ HL-WT mice. (8, 14, 31-34, 36 -38) and animal (40,44,45) studies indicate that the multiple functions of HL can lead to variable and sometimes opposing effects on lesion development, resulting in unpredictable changes in atherosclerosis. To date, the specific contribution of the ligand-binding function of HL to these various processes and especially to atherosclerosis has not been elucidated.…”

Section: Figmentioning

confidence: 99%

“…However, in both species, HL also leads to the formation of potentially small, dense, pro-atherogenic LDL (41)(42)(43). 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).…”

mentioning

confidence: 94%

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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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Section: Catalytically Inactive Hl-s145g Alters the Plasma Lipid Profsupporting

confidence: 93%

Section: Figmentioning

confidence: 85%

Section: Catalytically Active Hl-wt and Inactive Hl-s145g Lower The Pmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 94%

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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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Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function

et al. 2014

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IMPORTANCE The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).OBJECTIVES To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.MAIN OUTCOME MEASURES Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTSThe patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.CONCLUSIONS AND RELEVANCE Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

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Use of Gene Transfer to Study HDL Remodeling

Oka

Chan

2007

High‐Density Lipoproteins

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Hepatic Lipase Deficiency Increases Plasma Cholesterol but Reduces Susceptibility to Atherosclerosis in Apolipoprotein E-deficient Mice

Cited by 111 publications

References 34 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

Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function

Use of Gene Transfer to Study HDL Remodeling

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