Biology subjects

Allen, R. M.

Publications and source records attributed to Allen, R. M..

4 recordsLinked to original sources

bioRxiv2026

Lipolysis of host triacylglyceride-rich lipoproteins creates a toxic microenvironment for Staphylococcus aureus

Staphylococcus aureus secretes lipases that hydrolyze glycerol esters to mitigate host detection and scavenge fatty acids for membrane synthesis, but exposure to host-derived polyunsaturated fatty acids (PUFA) can be toxic. Here, we show that host hyperlipidemia protects against S. aureus osteomyelitis by engaging this vulnerability. Using a mouse model of severe hyperlipidemia, we show that PUFA-enriched plasma triacylglycerides are associated with reduced bacterial burden and bone destruction from injury-associated osteomyelitis. In vitro, human triacylglyceride-rich lipoproteins (TRL) exhibit potent bactericidal activity against post-exponential S. aureus that requires lipase activity of glycerol ester hydrolase (geh). Pre-exponential exposure to TRL suppressed agr quorum-sensing, blunting geh expression and toxicity; however, bactericidal activity of TRL could be restored by exogenous lipoprotein lipase. Together, these findings reveal TRL as active antimicrobial particles whose toxicity is unmasked by lipolysis and suggest that modulation of host lipid metabolism may provide new therapeutic opportunities for chronic S. aureus infection.

microbiology↗

bioRxiv2021

Physico-chemical principles of HDL-small RNA binding interactions.

Extracellular small RNAs (sRNA) are abundant in many biofluids, but little is known about their mechanisms of transport and stability in RNase-rich environments. We previously reported that high-density lipoproteins (HDL) of mice were enriched with multiple classes of sRNA derived from the endogenous transcriptome, but also exogenous organisms. Here, we show that human HDL transports tRNA-derived sRNAs (tDRs) from host and non-host species which were found to be altered in human atherosclerosis. We hypothesized that HDL binds to tDRs through apolipoprotein A-I (apoA-I) and these interactions are conferred by RNA-specific features. We tested this using microscale thermophoresis and electrophoretic mobility shift assays and found that HDL bind tDRs and other single-stranded sRNAs with strong affinity, but not doublestranded RNA or DNA. Natural and synthetic RNA modifications influenced tDR binding to HDL. Reconstituted HDL bound tDRs only in the presence of apoA-I and purified apoA-I alone was sufficient for binding sRNA. Conversely, phosphatidylcholine vesicles did not bind tDRs. In summary, HDL preferentially binds to single-stranded sRNAs likely through non-ionic interactions with apoA-I. These studies highlight binding properties that likely enable extracellular RNA communication and provide a foundation for future studies to manipulate HDL-sRNA for therapeutic approaches to prevent or treat disease.

molecular biology↗

bioRxiv2019

Statins Stimulate Hepatic Glucose Production via the miR-183/96/182 Cluster

Statins are the most common pharmacologic intervention in hypercholesterolemic patients, and their use is recognized as a key medical advance leading to a 50% decrease in deaths from heart attack or stroke over the past 30 years. The atheroprotective outcomes of statins are largely attributable to the accelerated hepatic clearance of low-density lipoprotein (LDL)-cholesterol from circulation, following the induction of the LDL receptor. However, multiple studies suggest that these drugs exert additional LDL-independent effects. The molecular mechanisms behind these so-called pleiotropic effects of statins, either beneficial or undesired, remain largely unknown. Here we determined the coding transcriptome, miRNome, and RISCome of livers from mice dosed with saline or atorvastatin to define a novel in vivo epitranscriptional regulatory pathway that links statins to hepatic gluconeogenesis, via the SREBP2-miR-183/96/182-TCF7L2 axis. Notably, multiple genome-wide association studies identified TCF7L2 (transcription factor 7 like 2) as a candidate gene for type 2 diabetes, independent of ethnicity. Conclusion: our data reveal an unexpected link between cholesterol and glucose metabolism, provides a mechanistic explanation to the elevated risk of diabetes recently observed in patients taking statins, and identifies the miR-183/96/182 cluster as an attractive pharmacological candidate to modulate non-canonical effects of statins.

cell biology↗

bioRxiv2018

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

To comprehensively study extracellular small RNAs (sRNA) by sequencing (sRNA-seq), we developed a novel pipeline to overcome current limitations in analysis entitled, \"Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER)\". To demonstrate the power of this tool, sRNA-seq was performed on mouse lipoproteins, bile, urine, and liver samples. A key advance for the TIGER pipeline is the ability to analyze both host and non-host sRNAs at genomic, parent RNA, and individual fragment levels. TIGER was able to identify approximately 60% of sRNAs on lipoproteins, and >85% of sRNAs in liver, bile, and urine, a significant advance compared to existing software. Results suggest that the majority of sRNAs on lipoproteins are non-host sRNAs derived from bacterial sources in the microbiome and environment, specifically rRNA-derived sRNAs from Proteobacteria. Collectively, TIGER facilitated novel discoveries of lipoprotein and biofluid sRNAs and has tremendous applicability for the field of extracellular RNA.

bioinformatics↗