Calcium Increases Apolipoprotein B mRNA Editing

Chen, Zhigang; Eggerman, Thomas L.; Potosky, Darryn; Arborati, Muriel; Patterson, Amy P.

doi:10.1006/bbrc.2000.3668

Cited by 11 publications

(8 citation statements)

References 37 publications

(31 reference statements)

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“…This RNA modification enables two functional protein products to be expressed from one gene [9; 10] (ApoB100 and ApoB48) that serve as scaffold proteins for lipoprotein particle assembly and transport of lipid from the liver and small intestine. Editing of apoB mRNA is a characteristic of differentiated tissue types [11] and is regulated hormonally [12] and metabolically [13; 14; 15; 16; 17; 18]. …”

Section: Introductionmentioning

confidence: 99%

Metabolic regulation of APOBEC-1 Complementation Factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes

Galloway¹,

Ashton²,

Sparks³

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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APOBEC-1 Complementation Factor (ACF) is an RNA-binding protein that interacts with apoB mRNA to support RNA editing. ACF traffics between the cytoplasm and nucleus. It is retained in the nucleus in response to elevated serum insulin levels where it supports enhanced apoB mRNA editing. In this report we tested whether ACF may have the ability to regulate nuclear export of apoB mRNA to the sites of translation in the cytoplasm. Using mouse models of obesity-induced, insulin resistance and primary hepatocyte cultures we demonstrated that both nuclear retention of ACF and apoB mRNA editing were reduced in the livers of hyperinsulinemic obese mice relative to lean controls. Coincident with an increase in the recovery of ACF in the cytoplasm was an increase in the proportion of total cellular apoB mRNA recovered in cytoplasmic extracts. Cytoplasmic ACF from both lean controls and obese mouse livers was enriched in endosomal fractions associated with apoB mRNA translation and ApoB lipoprotein assembly. Inhibition of ACF export to the cytoplasm resulted in nuclear retention of apoB mRNA and reduced both intracellular and secreted ApoB protein in primary hepatocytes. The importance of ACF for modulating ApoB was supported by the finding that RNAi knockdown of ACF reduced ApoB secretion. An additional discovery from this study was the finding that leptin is a suppressor ACF expression. Dyslipidemia is a common pathology associated with insulin resistance that is in part due to the loss of insulin controlled secretion of lipid in ApoB-containing very low density lipoproteins. The data from animal models suggested that loss of insulin regulated ACF trafficking and leptin regulated ACF expression may make an early contribution to the overall pathology associated with very low-density lipoprotein secretion from the liver in obese individuals.

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Section: Introductionmentioning

confidence: 99%

Metabolic regulation of APOBEC-1 Complementation Factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes

Galloway¹,

Ashton²,

Sparks³

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Many factors have been reported to be able to regulate apoB mRNA editing in the rodent liver or hepatic cells. In addition to the developmental stage (15,39), interventions such as growth hormones, estrogen, thyroid hormones, insulin, fasting, carbohydrate refeeding, treatment with ethanol, modulation of calcium concentration, and phosphorylation status affect editing (8,9,12,14,27,30). However, the exact molecular mechanisms that regulate apoB mRNA editing activity remain largely unclear.…”

mentioning

confidence: 99%

ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components

Chen

Eggerman²,

Patterson³

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Chen Z, Eggerman TL, Patterson AP. ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components. Am J Physiol Gastrointest Liver Physiol 292: G53-G65, 2007. First published August 17, 2006; doi:10.1152/ajpgi.00118.2006.-Apolipoprotein (apo)B mRNA editing is accomplished by a large multiprotein complex. How these proteins interact to achieve the precise single-nucleotide change induced by this complex remains unclear. We investigated the relationship between altered apoB mRNA editing and changes in editing enzyme components to evaluate their roles in editing regulation. In the mouse fetal small intestine, we found that the dramatic developmental upregulation of apoB mRNA editing from ϳ3% to 88% begins with decreased levels of inhibitory CUG binding protein 2 (CUGBP2) expression followed by increased levels of apoB mRNA editing enzyme (apobec)-1 and apobec-1 complementation factor (ACF) (4-and 8-fold) and then by decreased levels of the inhibitory components glycine-arginine-tyrosine-rich RNA binding protein (GRY-RBP) and heterogeneous nuclear ribonucleoprotein (hnRNP)-C1 (75% and 56%). In contrast, the expression of KH-type splicing regulatory protein (KSRP), apobec-1 binding protein (ABBP)1, ABBP2, and Bcl-2-associated athanogene 4 (BAG4) were unaltered. In the human intestinal cell line Caco-2, the increase of apoB mRNA editing from ϳ1.7% to ϳ23% was associated with 6-and 3.2-fold increases of apobec-1 and CUGBP2, respectively. In the mouse large intestine, the editing was 48% and had a 2.7-fold relatively greater CUGBP2 level. Caco-2 and the large intestine thus have increased instead of decreased CUGBP2 and a lower level of editing, suggesting that inhibitory CUGBP2 may play a critical role in the magnitude of editing regulation. Short interfering RNA-mediated gene-specific knockdown of CUGBP2, GRY-RBP, and hnRNP-C1 resulted in increased editing in Caco-2 cells, consistent with their known inhibitory function. These data suggest that a coordinated expression of editing components determines the magnitude and specificity of apoB mRNA editing. apolipoprotein; development; apolipoprotein B mRNA editing enzyme; apolipoprotein B mRNA editing enzyme-1 complementation factor; CUG binding protein-2 APOLIPOPROTEIN B (apoB) plays a central role in lipoprotein metabolism (40). ApoB protein exists mainly in two isoforms: apoB-48 and apoB-100. Only synthesized by the intestine in the human, apoB-48 is essential for the assembly of chylomicrons and has an obligatory role in the intestinal absorption of dietary fats. ApoB-100, which is produced in the liver in humans, is required for the synthesis and secretion of VLDL (40). ApoB-100 is virtually the only protein component of LDLs, which are metabolic products of VLDL and contain about two-thirds of the cholesterol in human plasma. Elevated concentrations of apoB-100 and LDL-cholesterol in plasma are recognized risk factors for developing atherosclerotic coronary artery disease (40).ApoB-48 is generated by the editing of apoB mR...

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“…RNA editing in these cells can be modulated after cellular differentiation by a number of stimuli. 45,67 We thus transduced Caco-2 cells with our fluorescent mCherry-ApoB-EGFP chimera through lentiviral infection and we induced RNA editing by treatment with Forskolin, a protein kinase activator which has been shown to induce RNA editing. 45 Indeed treatment with 250 mM Forskolin induced a gradual increase in editing, proportional to the exposure (Fig.…”

Section: Detection Of Rna Editing In Induced Caco-2 Cellsmentioning

confidence: 99%

“…42,43 In addition ApoB RNA editing in Caco-2 cells can be induced by calcium or other stimuli. 44,45 A number of assays have been developed to measure the efficiency of APOBEC1-dependent RNA editing in cells and organ extracts. 39,[46][47][48][49][50] The most commonly used assays are based either on sequence analysis or on poisoned primer extension of the edited site.…”

Section: Introductionmentioning

confidence: 99%

Flow-cytometric visualization of C>U mRNA editing reveals the dynamics of the process in live cells

Severi

Conticello

2015

RNA Biology

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APOBEC1 is the catalytic subunit of the complex that edits ApolipoproteinB (ApoB) mRNA, which specifically deaminates cytidine 6666 to uracil in the human transcript. The editing leads to the generation of a stop codon, resulting in the synthesis of a truncated form of ApoB. We have developed a method to quantitatively assay ApoB RNA editing in live cells by using a double fluorescent mCherry-EGFP chimera containing a »300bp fragment encompassing the region of ApoB subject to RNA editing. Coexpression of APOBEC1 together with this chimera causes specific RNA editing of the ApoB fragment. The insertion of a stop codon between the mCherry and EGFP thus induces the loss of EGFP fluorescence. Using this method we analyze the dynamics of APOBEC1-dependent RNA editing under various conditions. Namely we show the interplay of APOBEC1 with known interactors (ACF, hnRNP-C1, GRY-RBP) in cells that are RNA editing-proficient (HuH-7) or -deficient (HEK-293T), and the effects of restricted cellular localization of APOBEC1 on the efficiency of the editing. Furthermore, our approach is effective in assaying the induction of RNA editing in Caco-2, a cellular model physiologically capable of ApoB RNA editing.

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Calcium Increases Apolipoprotein B mRNA Editing

Cited by 11 publications

References 37 publications

Metabolic regulation of APOBEC-1 Complementation Factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes

Metabolic regulation of APOBEC-1 Complementation Factor trafficking in mouse models of obesity and its positive correlation with the expression of ApoB protein in hepatocytes

ApoB mRNA editing is mediated by a coordinated modulation of multiple apoB mRNA editing enzyme components

Flow-cytometric visualization of C>U mRNA editing reveals the dynamics of the process in live cells

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