Complete Prevention of Atherosclerosis in ApoE-Deficient Mice by Hepatic Human ApoE Gene Transfer With Adeno-Associated Virus Serotypes 7 and 8

Kitajima, Ken; Marchadier, Dawn; Miller, Gwen C.; Gao, Guangping; Wilson, James M.; Rader, Daniel J.

doi:10.1161/01.atv.0000231520.26490.54

Cited by 49 publications

(38 citation statements)

References 38 publications

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“…Because the Cre recombinase expression was driven by the liver-specific thyroxine-binding globulin promoter (12), the AAV approach resulted in sustained Cre expression in the liver for at least 20 weeks (13).…”

Section: Methodsmentioning

confidence: 99%

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knock-out mice. We produced Lpcat3-Flox/villin-Cre-ER T2 mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to delete Lpcat3 specifically in the small intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated phosphatidylcholines in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reducing lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adenovirus-associated virus-Cre to deplete Lpcat3 in the liver. We found that liver deficiency only reduces plasma triglyceride levels but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has a much bigger effect on plasma lipid levels than that of liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.The majority of lipids on the cell membrane as well as the plasma lipoproteins are phospholipids, in particular phosphatidylcholines (PCs) 2 (1, 2). Monounsaturated and saturated fatty acids are usually esterified at the sn-1 position of PCs, whereas polyunsaturated fatty acids are esterified at the sn-2 position (3). The asymmetric distribution of fatty acids at the sn-1 and sn-2 positions of PCs is maintained in part by a deacylationreacylation process known as the Lands cycle or PC remodeling (3, 4). One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9, 10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9). Because of neonatal lethality (non-inducible approach was utilized), only 1-week-old newborns were analyzed for the impact of intestine-specific Lpcat3 deficiency on lipid metabolism (9). Very recently, we found that...

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Section: Methodsmentioning

confidence: 99%

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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“…The cis-plasmids pAAV.TBG.EL.WT and pAAV. TBG.EL.Asn396Ser were created by cloning the coding region from the EL expression plasmid described above into the pAAV.TBG cis-plasmid (54). The AAV2/8-EL.WT and AAV2/8-EL.Asn396Ser viruses were produced by triple transfection into 293 cells, with an adenovirus helper plasmid and a chimeric packaging construct in which the AAV2 rep gene is fused with the cap gene of serotype 8.…”

Section: Methodsmentioning

confidence: 99%

Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

Edmondson¹,

Brown²,

Kathiresan³

et al. 2009

J. Clin. Invest.

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116

144

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Elevated plasma concentrations of HDL cholesterol (HDL-C) are associated with protection from atherosclerotic cardiovascular disease. Animal models indicate that decreased expression of endothelial lipase (LIPG)is inversely associated with HDL-C levels, and genome-wide association studies have identified LIPG variants as being associated with HDL-C levels in humans. We hypothesized that loss-of-function mutations in LIPG may result in elevated HDL-C and therefore performed deep resequencing of LIPG exons in cases with elevated HDL-C levels and controls with decreased HDL-C levels. We identified a significant excess of nonsynonymous LIPG variants unique to cases with elevated HDL-C. In vitro lipase activity assays demonstrated that these variants significantly decreased endothelial lipase activity. In addition, a meta-analysis across 5 cohorts demonstrated that the low-frequency Asn396Ser variant is significantly associated with increased HDL-C, while the common Thr111Ile variant is not. Functional analysis confirmed that the Asn396Ser variant has significantly decreased lipase activity both in vitro and in vivo, while the Thr111Ile variant has normal lipase activity. Our results establish that loss-of-function mutations in LIPG lead to increased HDL-C levels and support the idea that inhibition of endothelial lipase may be an effective mechanism to raise HDL-C.

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“…ApoE promotes the clearance of atherogenic lipoproteins ( 6,7,10 ), and also a number of pleiotropic effects of apoE might be important. For example, apoE has antioxidative properties.…”

Section: Probucol Treatment Increases Macrophage-to-feces Rct In Apoementioning

confidence: 99%

ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

Annema

Dikkers

Boer

et al. 2012

Journal of Lipid Research

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Apolipoprotein E (apoE) plays an important role in lipo protein metabolism and atherosclerosis. ApoE is produced and secreted predominantly by the liver ( 1 ), but it is also expressed in a variety of other tissues, including macrophages ( 2, 3 ). While loss of function of apoE in mice and in humans is associated with a proatherogenic lipoprotein profi le and increased atherogenesis ( 4, 5 ), overexpression of apoE in various models has been shown to protect against atherosclerotic lesion formation ( 6-11 ). Among other metabolic effects that are potentially antiatherogenic, apoE has been reported to promote cholesterol effl ux (12)(13)(14), and recent studies have suggested that lack of macrophage apoE might decrease overall reverse cholesterol transport (RCT) ( 15 ). However, the pool of macrophage-derived apoE represents a small fraction of total circulating apoE.The classic RCT pathway is a multistep process that involves i ) HDL-mediated effl ux of excess cholesterol from extrahepatic cells and most relevant for atherosclerosis lipid-laden macrophages in the arterial wall, ii ) uptake of HDL cholesterol into the liver, and iii ) excretion of HDL Abstract ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirusmediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased ( P < 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confi rmed using SR-BI-defi cient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates ( P < 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice ( P < 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with 3 H-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol effl ux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion ( P < 0.05), fecal neutral sterol excretion ( P < 0.05), and in vivo RCT ( P < 0.01), specifi cally within neutral sterols. These combined data demonstrate that systemic apoE overexpression increases i ) SR-BI-mediated selective uptake into the liver and ii ) ABCA1-mediated effl ux of RCTrelevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT. -Annema, W., A. Dikkers, J. F. de Boer, T. Gautier, P. C. N. Rensen, D. J. Rader, and U. J. F. Tietge. ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol effl ux to plasma. J. Lipid Res . 2012. 53: 929-940. 29 February 2012. Published, JLR Pap...

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Complete Prevention of Atherosclerosis in ApoE-Deficient Mice by Hepatic Human ApoE Gene Transfer With Adeno-Associated Virus Serotypes 7 and 8

Cited by 49 publications

References 38 publications

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans

ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

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