Ethanol Stimulates Apolipoprotein B mRNA Editing in the Absence of de Novo RNA or Protein Synthesis

Giangreco, Adam; Sowden, Mark P.; Mikityansky, Igor; Smith, Harold C.

doi:10.1006/bbrc.2001.6082

Cited by 10 publications

(9 citation statements)

References 35 publications

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“…Trafficking of ACF64-APOBEC-1 complexes between active nuclear 27 S complexes and inactive 60 S complexes would provide a rapid and reversible mechanism for regulating apoB mRNA editing that requires little or no de novo protein synthesis. In this regard, the regulation of apoB mRNA editing by ethanol is independent of continued protein or RNA synthesis (74). Alterations in the relative abundance of nuclear and cytoplasmic localized ACF64 have been documented for four metabolic conditions: insulin-or ethanoltreated rat primary hepatocytes (28), thyroid hormone administration (72), and in liver of fasted and refed rats (this report).…”

Section: Discussionmentioning

confidence: 81%

Identification of Novel Alternative Splice Variants of APOBEC-1 Complementation Factor with Different Capacities to Support Apolipoprotein B mRNA Editing

Sowden

Lehmann

Lin

et al. 2004

Journal of Biological Chemistry

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Two novel mRNA transcripts have been identified that result from species-and tissue-specific, alternative polyadenylation and splicing of the pre-mRNA encoding the apolipoprotein B (apoB) editing catalytic subunit 1 (APOBEC-1) complementation factor (ACF) family of related proteins. The alternatively processed mRNAs encode 43-and 45-kDa proteins that are components of the previously identified p44 cluster of apoB RNA binding, editosomal proteins. Recombinant ACF45 displaced ACF64 and ACF43 in mooring sequence RNA binding but did not demonstrate strong binding to APOBEC-1. In contrast, ACF43 bound strongly to APOBEC-1 but demonstrated weak binding to mooring sequence RNA. Consequently ACF45/43 complemented APOBEC-1 in apoB mRNA editing with less efficiency than full-length ACF64. These data, together with the finding that all ACF variants were co-expressed in rat liver nuclei (the site of apoB mRNA editing), suggested that ACF variants might compete with one another for APOBEC-1 and apoB mRNA binding and thereby contribute to the regulation of apoB mRNA editing. In support for this hypothesis, the ratio of nuclear ACF65/64 to ACF45/43 decreased when hepatic editing was inhibited by fasting and increased when editing was re-stimulated by refeeding. These findings suggested a new model for the regulation of apoB mRNA editing in which the catalytic potential of editosomes is modulated at the level of their assembly by alterations in the relative abundance of multiple related RNA-binding auxiliary proteins and the expression level of APOBEC-1.Alternative mRNA polyadenylation, splicing, and mRNA editing are mechanisms of post-transcriptional RNA processing that introduce diversity in mammalian mRNAs, thereby regulating the number of structurally and functionally different proteins encoded by a single gene (reviewed in Refs. 1 and 2). Base modification RNA editing may involve the enzymatic deamination of single nucleotides within splice site consensus motifs (3) or in protein coding sequence, often with physiologically significant effects (4). Adenosine to inosine editing of mRNAs, such as that occurring on mRNAs encoding the glutamate-gated calcium channel and serotonin 2C receptor subunits, is mediated by a family of adenosine deaminases active on RNAs that function independently of cofactors to deaminate their cognate target within double-stranded RNA (reviewed in Ref. 5). Multiple cytidine deaminases active on RNA have been predicted through their homology with the zinc-dependent cytidine deaminase domain of the mRNA editing enzyme APO-BEC-1 1 (Ref. 6 and references therein); however, only APO-BEC-1 (7, 8) and CDD1 (9) have been shown to deaminate cytidines within mRNA. Unlike adenosine deaminases active on RNA, cytidine deaminases active on RNA minimally require RNA-binding auxiliary proteins for their activity on RNA.Cytidine to uridine deamination of nucleotide 6666 of apolipoprotein B mRNA occurs in the small intestine of all, and the livers of some, mammalian species (10 -12). The glutaminespecifying CAA codon...

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Section: Discussionmentioning

confidence: 81%

Identification of Novel Alternative Splice Variants of APOBEC-1 Complementation Factor with Different Capacities to Support Apolipoprotein B mRNA Editing

Sowden

Lehmann

Lin

et al. 2004

Journal of Biological Chemistry

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“…Changes in ApoB secretion are thought to occur primarily as a consequence of post-transcriptional mechanisms, as the apob gene is considered to be constitutively expressed. Although a number of studies have demonstrated that ApoB mRNA content can vary in response to certain stimuli in vitro in HepG2 cells [7,8,10], rat hepatocytes [41] and CaCo-2 cells [10,42,43], and in vivo [6], reported changes are relatively small. In the present study, we demonstrate substantial increases in apob gene transcription induced by dietary betaine.…”

Section: Discussionmentioning

confidence: 99%

“…As a compensatory mechanism for the reduced activity of methionine synthase with ethanol feeding, there is an adaptive increase in liver BHMT that serves to maintain adequate levels of hepatic SAM [57]. Short-term ethanol treatment has been shown in separate studies to increase significantly ApoB mRNA content in HepG2 cells [8], and in rat hepatocytes [41], although other studies have not seen this relationship with chronic feeding [58]. Because high expression levels of BHMT in McA cells alone produced increases in ApoB mRNA similar to those observed by dietary induction of BHMT, current results point specifically to the importance of BHMT in this process.…”

Section: Discussionmentioning

confidence: 99%

Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine–homocysteine S-methyltransferase

Sparks

Collins

Chirieac

et al. 2006

Biochemical Journal

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We have previously reported a positive correlation between the expression of BHMT (betaine-homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639-645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion.

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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.…”

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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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Ethanol Stimulates Apolipoprotein B mRNA Editing in the Absence of de Novo RNA or Protein Synthesis

Cited by 10 publications

References 35 publications

Identification of Novel Alternative Splice Variants of APOBEC-1 Complementation Factor with Different Capacities to Support Apolipoprotein B mRNA Editing

Identification of Novel Alternative Splice Variants of APOBEC-1 Complementation Factor with Different Capacities to Support Apolipoprotein B mRNA Editing

Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine–homocysteine S-methyltransferase

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

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