The Expression of Intact and Mutant Human apoAI/CIII/AIV/AV Gene Cluster in Transgenic Mice

Gao, Jun; Wei, Yu‐Sheng; Huang, Yue; Liu, Depei; Guang, Liu; Wu, Min; Zhang, Qingjun; Zhang, Zhuqin; Zhang, Ran; Liang, Chih‐Chuan

doi:10.1074/jbc.m409883200

Cited by 16 publications

(20 citation statements)

References 34 publications

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“…Downexpression of apoc3, but not apoa4, results from interference by the nearby neomycin resistance cassette (14,21). In contrast, apoa5 gene expression was found to be normal in Apoa1/c3/a4 mice (data not shown) and so likely in Apoa1 2/2 mutants, consistent with transgenic studies showing that the apoC-III enhancer regulates the expression of apoA-I, apoC-III, and apoA-IV but not apoA-V in vivo (36). These data demonstrate that Apoa1 2/2 mice are apoA-I/C-III-deficient and differ from Apoa1/c3/a4 2/2 mice mostly by the presence of apoA-IV.…”

Section: Discussionsupporting

confidence: 70%

Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency

Mezdour

Larigauderie

Castro

et al. 2006

Journal of Lipid Research

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Human data raised the possibility that coronary heart disease is associated with mutations in the apolipoprotein gene cluster APOA1/C3/A4 that result in multideficiency of cluster-encoded apolipoproteins and hypoalphalipoproteinemia. To test this hypothesis, we generated a mouse model for human apolipoprotein A-I (apoA-I)/C-III/A-IV deficiency. Homozygous mutants (Apoa1/c3/a4 2/2 ) lacking the three cluster-encoded apolipoproteins were viable and fertile. In addition, feeding behavior and growth were apparently normal. Total cholesterol (TC), high density lipoprotein cholesterol (HDLc), and triglyceride levels in the plasma of fasted mutants fed a regular chow were 32% (P , 0.001), 17% (P , 0.001), and 70% (P , 0.01), respectively, those of wild-type mice. When fed a high-fat Western-type (HFW) diet, Apoa1/ c3/a4 2/2 mice showed a further decrease in HDLc concentration and a moderate increase in TC, essentially in non-HDL fraction. The capacity of Apoa1/c3/a4 2/2 plasma to promote cholesterol efflux in vitro was decreased to 75% (P , 0.001), and LCAT activity was decreased by 38% (P , 0.01). Despite the very low total plasma cholesterol, the imbalance in lipoprotein distribution caused small but detectable aortic lesions in one-third of Apoa1/c3/a4 2/2 mice fed a HFW diet. In contrast, none of the wild-type mice had lesions. These results demonstrate that Apoa1/c3/a4 2/2 mice display clinical features similar to human apoA-I/C-III/A-IV deficiency (i.e., marked hypoalphalipoproteinemia) and provide further support for the apoa1/c3/a4 gene cluster as a minor susceptibility locus for atherosclerosis in mice. Supplementary key words apoa1/c3/a4 gene cluster (mouse) . APOA1/ C3/A4 gene cluster (human) . knockout mouse . hypoalphalipoproteinemia . high-fat Western-type diet . atherosclerosis A strong inverse association exists between plasma high density lipoprotein cholesterol (HDLc) levels and the incidence of coronary artery disease in humans (1). The major locus controlling HDLc levels is APOA1 (for apolipoprotein A-I), a member of the apolipoprotein gene cluster APOA1/C3/A4 (2). The cluster genes, APOA1, APOC3, and APOA4, are evolutionarily related and tandemly organized in a region of 17 kb DNA on human chromosome 11, proximal to APOA5, a new member of the apolipoprotein gene family (3). These APOA1/C3/A4 genes code for three apolipoproteins, apoA-I, apoC-III, and apoA-IV, respectively. ApoA-I is a 28 kDa protein synthesized in the liver and small intestine (4). It is the major protein component of HDL. Through its ability to promote cholesterol efflux from cultured cells (5) and to activate LCAT (6), apoA-I plays a key role in reverse cholesterol transport, a mechanism postulated to prevent extrahepatic tissues from accumulating excess cholesterol (7). Apolipoprotein C-III is a 9 kDa protein produced predominantly in the liver. It is a major component of plasma chylomicrons and VLDL. ApoC-III inhibits the hydrolysis of triglyceride by lipoprotein lipase. Apolipoprotein A-IV is a 46 kDa protein associat...

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Section: Discussionsupporting

confidence: 70%

Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency

Mezdour

Larigauderie

Castro

et al. 2006

Journal of Lipid Research

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“…23 Mouse Breeding, Diet, and Analysis of Atherosclerotic Lesions PC Tg mice were crossed with ApoE-null mice to obtain PC Tg/ApoE-null mice and ApoE-null littermates, which were maintained on chow diet for 6 weeks and then switched to a Western diet containing 10% fat and 1.25% cholesterol to induce atherogenesis. En face aorta atherosclerotic lesions were analyzed as described.…”

Section: Construction Of Human Pon Cluster Transgenic Micementioning

confidence: 99%

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

She

Zheng

Wei

et al. 2009

Circulation Research

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Abstract-The paraoxonase (PON) gene cluster consists of the PON1, PON2, and PON3 genes, each of which canindividually inhibit atherogenesis. To analyze the functions of the PON gene cluster (PC) in atherogenesis and plaque stability, human PC transgenic (Tg) mice were generated using bacterial artificial chromosome. The high-density lipoprotein from Tg mice exhibited increased paraoxonase activity. When crossed to the ApoE-null background and challenged by high-fat diet, PC Tg/ApoE-null mice formed significantly fewer atherosclerotic lesions. However overexpression of the PC transgene had no additive effect on atherosclerosis compared to the overexpression of the single PON1 or PON3 transgene. Plaques from PC Tg/ApoE-null mice exhibited increased levels of collagen and smooth muscle cells, and reduced levels of macrophages and lipid, compared with those from ApoE-null mice, indicating lesions of PC Tg/ApoE-null mice had characteristics of more stable plaques than those of ApoE-null mice. PC transgene enhanced high-density lipoprotein ability to protect low-density lipoprotein against oxidation in vitro. Serum intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were also repressed by PC transgene. Proatherogenic reactions of Tg mouse peritoneal macrophages induced by oxidized low-density lipoprotein were inhibited by PC transgene, as indicated by reduced reactive oxygen species generation, inflammation, matrix metalloproteinase-9 expression, and foam cell formation. Our results demonstrate that the PC transgene not only represses atherogenesis but also promotes atherosclerotic plaque stability in vivo. PC may therefore be a useful target for atherosclerosis treatment. Key Words: atherosclerosis Ⅲ plaques stability Ⅲ macrophages Ⅲ paraoxonase cluster A therosclerosis constitutes the single most important contributor to cardiovascular diseases, which are the leading cause of death and illness in developed societies. 1,2 Atherosclerosis-related ischemic symptoms, especially acute cardiovascular events that result in myocardial infarction and stroke, are generally thought to result from plaque rupture and thrombosis other than narrowing of the vessel lumen. 3 New strategies for preventing and treating plaque rupture are very much needed based on understanding of factors that contributed. Oxidized low-density lipoprotein (oxLDL) plays a pivotal role in triggering proinflammatory events that initiate and exacerbate atherogenesis, 1,4 which induces the expression of adhesion molecules, chemokines, and cytokines in vascular endothelial cells, 5 triggering recruitment of monocytes into the subendothelial space of the arterial wall, where they differentiate into macrophages. Recruited macrophages ingest and further oxidize LDL, transforming into foam cell after excessive oxLDL accumulation. These transformed macrophages not only constitute early fatty streak lesions and the core of atherosclerotic plaques but also become active inflammation centers because of secretion of inflammatory molecules and ma...

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“…A recent study showing that the APOC3-enhancer that affects expression of the APOA1, APOC3, and APOA4 genes does not up-regulate transcription of the APOA5 gene (Gao et al 2005) provided some insight into this issue, but several points remain uncertain. For example, it is unclear why the APOC3-enhancer is not able to act upon the APOA5-promoter that is just 35 kb away, when it is known that eukaryotic enhancers may exert their effects up to a distance of 100-kb (Zhao and Dean 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the distal APOC3-enhancer can regulate tissue-specific expression of the three APOA1, APOA4, and APOC3 genes (Ogami et al 1990;Ktistaki et al 1994;Zannis et al 2001). A recent study found that this common enhancer did not regulate in vivo APOA5 expression (Gao et al 2005), which agrees with much lower plasma levels of apoAV compared to other apolipoproteins (O'Brien et al 2005). For example, plasma apoAV levels (24-406 lg/l) (O'Brien et al 2005) are 1,000-2,000-fold-lower than human apoCIII plasma concentrations (50-140 mg/l) (Marz et al 1987;Sakurabayashi et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary rate heterogeneity of Alu repeats upstream of the APOA5 gene: do they regulate APOA5 expression?

Ruiz-Narváez

Campos

2008

J Hum Genet

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The APOA5 gene, located in the APOA1/C3/A4/ A5 gene cluster, is a key regulator of triglyceride metabolism. ApoAV plasma concentration is much lower as compared to other apolipoproteins such as apoCIII and apoAI. This is due in part to the fact that the APOC3-enhancer, which up-regulates transcription of the APOA1, APOC3, and APOA4 genes, does not increase expression of the APOA5 gene. We postulated that intervening Alu repeats in the APOA5-APOA4 intergenic region gene might be blocking action of the APOC3-enhancer over the APOA5-promoter. To search for evidence of functional significance of the intervening Alu sequences, we estimated nucleotide substitution rates of 21 pairs of Alu elements in the APOA5-APOA4 intergenic region by comparing published sequences of human and chimpanzee. Also, we scanned the intergenic region for the presence of binding sites of the insulator protein CTCF. Seven out of the nine found CTCF binding sites were located in the first half of the intergenic region. Five out of those seven CTCF binding sites were placed inside Alu elements. Based on their substitution rates, we found two clearly defined groups of Alu sequences: a slow-evolving group (mean 0.98 ± 0.18) and a fast-evolving group (mean 2.74 ± 0.54). Alu repeats with lower substitution rate tended to be located up to 14-kb upstream of the APOA5 gene, to belong to the oldest J-family and to have an opposite orientation to the APOA5 gene. Some Alu sequences may have functional relevance on the regulation of the APOA5-gene expression.

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The Expression of Intact and Mutant Human apoAI/CIII/AIV/AV Gene Cluster in Transgenic Mice

Cited by 16 publications

References 34 publications

Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency

Characterization of a new mouse model for human apolipoprotein A-I/C-III/A-IV deficiency

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

Evolutionary rate heterogeneity of Alu repeats upstream of the APOA5 gene: do they regulate APOA5 expression?

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