Modulation of AKAP12 in the liver regulates lipid homeostasis and inflammation
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ABSTRACT:
PROVIDER: PRJNA1226945 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32514903_1.fastq.gz | Fastqsanger.gz | |||
| SRR32514903_2.fastq.gz | Fastqsanger.gz | |||
| SRR32514904_1.fastq.gz | Fastqsanger.gz | |||
| SRR32514904_2.fastq.gz | Fastqsanger.gz | |||
| SRR32514905_1.fastq.gz | Fastqsanger.gz |
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Project description:Dysregulation of lipid homeostasis is a feature of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). We examined how AKAP12’ could regulate alcohol-associated steatosis. Alcohol exposure reduced AKAP12’s interaction with PKA and suppressed PKA activation. Forced expression of AKAP12 overcame the suppression of PKA activity in human hepatocytes and in livers of mice exposed to alcohol. This led to a decrease in hepatic steatosis. Disrupting the scaffold of AKAP12 and PKA by CRISPR editing increased steatosis and inflammation. RNA sequencing analysis of hepatocytes from alchol fed mice and normal mice demonstrated key lipogenic and inflammatory pathways regulated by AKAP12 overexpression. RNA sequencing of total liver from mice with AKAP12-PKA binding site CRISPR editing or AKAP12 overexpression confirmed regulation of lipogenic and inflammatory pathways by AKAP12
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Project description:This study investigates the role of AKAP12 in endothelial cell motility with a specific focus on AKAP12 variants, AKAP12v1 and AKAP12v2. Previous work has shown that AKAP12, a multivalent A-kinase anchoring protein that binds to PKA and several other proteins regulating protein phosphorylation, is expressed at low levels in most endothelia in vivo but is expressed at higher levels in cells in vitro. Here, we found that AKAP12 expression in endothelial cell (HUVEC) cultures was cell density-dependent, with the expression being highest in subconfluent cultures and lowest in confluent cultures. AKAP12 expression was also elevated in cells at the wound edge of wounded endothelial cell monolayers. Knockdown of variants 1 and 2 inhibited cell migration. However, CRISPR/Cas9 knockout of AKAP12v1 enhanced migration, indicating that the absence of this variant and the presence of AKAP12v2 likely alters the signaling events controlling cell motility. Further analysis using bulk RNA sequencing revealed that the loss of AKAP12v1 affected genes associated with cell migration and intercellular junctions. We propose that AKAP12v1 and AKAP12v2 play distinct yet complementary roles in endothelial cell migration and likely work together in controlling the signaling events associated with vascular repair and development.
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Project description:Regulation of subcellular mRNA localisation is a fundamental biological mechanism, which adds a spatial dimension to the diverse layers of post-transcriptional control of gene expression. Insights into this phenomenon have been described in a multitude of cell types and across taxonomic kingdoms, highlighting its biological significance. The cellular compartment in which mRNAs are located may define distinct aspects of the encoded proteins, ranging from production rate and complex formation to localised activity. Ultimately, mRNA localisation supports compartmentalised mechanistic outputs that can respond to local stimuli, orient migration, or even shape cells. We used an unbiased method to profile the RNA-bound proteome in migrating endothelial cells and found that the plasma membrane (PM)-associated A-kinase anchor protein 12 (AKAP12) interacts with various mRNAs, including mRNAs encoding kinases with Actin remodelling activity. To identify transcripts bound by AKAP12, we carried out UV crosslinking experiments followed by RNA immunoprecipitation and high throughput sequencing. Our data offer novel insights in complex mechanisms of spatial control of gene expression.
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