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RNA-binding protein A1CF modulates plasma triglyceride levels through posttranscriptional regulation of stress-induced VLDL secretion

Jennie Lin, Donna M. Conlon, Xiao Wang, Eric Van Nostrand, Ines Rabano, YoSon Park, Alanna Strong, Behram Radmanesh, Yoseph Barash, Daniel J. Rader, Gene W. Yeo, Kiran Musunuru
doi: https://doi.org/10.1101/397554
Jennie Lin
1Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
2Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Donna M. Conlon
3Division of Translational Medicine and Human Genetics of the Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Xiao Wang
4Cardiovascular Institute of the Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Eric Van Nostrand
5Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
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Ines Rabano
5Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
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YoSon Park
6Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Alanna Strong
7Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
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Behram Radmanesh
1Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Yoseph Barash
6Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Daniel J. Rader
3Division of Translational Medicine and Human Genetics of the Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
6Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
7Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
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Gene W. Yeo
5Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA
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Kiran Musunuru
4Cardiovascular Institute of the Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
6Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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ABSTRACT

Background A recent human exome-chip study on plasma lipids identified a missense mutation in the A1CF (APOBEC1 complementation factor) gene that is associated with elevated triglyceride (TG) levels, but how A1CF, an RNA binding protein, influences plasma TG is unknown.

Methods We generated A1cf knockout (A1cf −/−) mice and knock-in mice homozygous for the TG-associated Gly398Ser mutation (A1cfGS/GS), determined lipid phenotypes, and assessed TG physiology through measurements of clearance and secretion. We further identified A1CF’s RNA binding targets using enhanced cross-linking and immunoprecipitation sequencing of cultured HepG2 cells and investigated pathways enriched for these targets. Transcriptomic effects of A1CF deficiency were evaluated through RNA sequencing and analyses for differential expression, alternative splicing, and RNA editing.

Results Both A1cf −/−and A1cfGS/GS mice exhibited increased fasting plasma TG, establishing that the TG phenotype is due to A1CF loss of function. In vivo TG secretion and clearance studies revealed increased TG secretion without changes in clearance in A1cf −/−mice. Increased VLDL-apoB secretion was also seen in A1cf −/−rat hepatoma cells, but no increase in apoB synthesis was observed. This phenotype was seen without significant shifts in apoB-100/apoB-48 in A1CF deficiency. To discover novel pathways for A1CF’s role in TG metabolism, we identified A1CF’s RNA binding targets, which were enriched for pathways related to proteasomal catabolism and endoplasmic reticulum (ER) stress. Indeed, proteasomal inhibition led to increased cellular stress in A1cf −/−cells, and higher expression of ER-stress protein GRP78 was observed in resting A1cf −/−cells. RNA-seq of whole livers from wild-type and A1cf −/−mice revealed that pro-inflammatory, not lipogenesis, genes were upregulated as a secondary effect of A1CF deficiency. Differential alternative splicing (AS) analysis and RNA editing analysis revealed that genes involved in cellular stress and metabolism underwent differential changes in A1CF deficiency, and top A1CF binding target proteins with relevance to intracellular stress were differentially expressed on the protein but not mRNA level, implicating multiple mechanisms by which A1CF influences TG secretion.

Conclusions These data suggest an important role for A1CF in mediating VLDL-TG secretion through regulating intracellular stress.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 22, 2018.
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RNA-binding protein A1CF modulates plasma triglyceride levels through posttranscriptional regulation of stress-induced VLDL secretion
Jennie Lin, Donna M. Conlon, Xiao Wang, Eric Van Nostrand, Ines Rabano, YoSon Park, Alanna Strong, Behram Radmanesh, Yoseph Barash, Daniel J. Rader, Gene W. Yeo, Kiran Musunuru
bioRxiv 397554; doi: https://doi.org/10.1101/397554
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RNA-binding protein A1CF modulates plasma triglyceride levels through posttranscriptional regulation of stress-induced VLDL secretion
Jennie Lin, Donna M. Conlon, Xiao Wang, Eric Van Nostrand, Ines Rabano, YoSon Park, Alanna Strong, Behram Radmanesh, Yoseph Barash, Daniel J. Rader, Gene W. Yeo, Kiran Musunuru
bioRxiv 397554; doi: https://doi.org/10.1101/397554

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