Biology subjects

Beier, J. I.

Publications and source records attributed to Beier, J. I..

3 recordsLinked to original sources

bioRxiv2023

The plasma degradome reflects later development of NASH fibrosis after liver transplant

Although liver transplantation (LT) is an effective therapy for cirrhosis, the risk of post-LT NASH is alarmingly high and is associated with accelerated progression to fibrosis/cirrhosis, cardiovascular disease, and decreased survival. Lack of risk stratification strategies hamper liver undergoes significant remodeling during inflammatory injury. During such remodeling, degraded peptide fragments (i.e., degradome) of the ECM and other proteins increase in plasma, making it a useful diagnostic/prognostic tool in chronic liver disease. To investigate whether inflammatory liver injury caused by post-LT NASH would yield a unique degradome profile, predictive of severe post-LT NASH fibrosis, we performed a retrospective analysis of 22 biobanked samples from the Starzl Transplantation Institute (12 with post-LT NASH after 5 years and 10 without). Total plasma peptides were isolated and analyzed by 1D-LC-MS/MS analysis using a Proxeon EASY-nLC 1000 UHPLC and nanoelectrospray ionization into an Orbitrap Elite mass spectrometer. Qualitative and quantitative peptide features data were developed from MSn datasets using PEAKS Studio X (v10). LC-MS/MS yielded [~]2700 identifiable peptide features based on the results from Peaks Studio analysis. Several peptides were significantly altered in patients that later developed fibrosis and heatmap analysis of the top 25 most significantly-changed peptides, most of which were ECM-derived, clustered the 2 patient groups well. Supervised modeling of the dataset indicated that a fraction of the total peptide signal ([~]15%) could explain the differences between the groups, indicating a strong potential for representative biomarker selection. A similar degradome profile was observed when the plasma degradome patterns were compared being obesity sensitive (C57Bl6/J) and insensitive (AJ) mouse strains. Both The plasma degradome profile of post-LT patients yields stark difference based on later development of post-LT NASH fibrosis. This approach could yield new "fingerprints" that can serve as minimally-invasive biomarkers of negative outcomes post-LT.

pathology↗

bioRxiv2022

Western diet unmasks transient low-level vinyl chloride exposure-induced tumorigenesis; potential role of the (epi-)transcriptome

Background & AimsVinyl chloride (VC) monomer is a volatile organic compound commonly used in industry to produce polyvinyl chloride (PVC). At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., < regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). Although these lower exposure levels are considered safe, it is unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. Low-concentration VC is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. MethodsC57Bl/6J mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding only, mice were also exposed to VC via inhalation at sub-regulatory limit concentrations (<1 ppm) or air for 6 hours/day, 5 days/week. ResultsFeeding WD for 1 year caused significant hepatic injury, including steatohepatitis and moderate fibrosis, which was exacerbated by VC. Additionally, VC increased the number of tumors which ranged from moderately to poorly differentiated hepatocellular carcinoma (HCC). Transcriptomic analysis demonstrated VC-induced changes in metabolic but also ribosomal processes. Epitranscriptomic analysis showed a VC-induced shift of the modification pattern that has been associated with metabolic disease, mitochondrial dysfunction, and cancer. ConclusionsThese data indicate that VC sensitizes the liver to other stressors (e.g., WD), resulting in enhanced tumorigenesis. These data raise concerns about a potential interaction between VC exposure and WD. Furthermore, it also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity.

cancer biology↗

bioRxiv2022

Fibrosis resolution involves more than collagen; new potential players of fibrosis recovery in mouse liver

Although most work has focused on resolution of collagen ECM, fibrosis resolution involves changes to several ECM proteins. The purpose of the current study was two-fold: 1) to examine the role of MMP12 and elastin; and 2) to investigate the changes in degraded proteins in plasma (i.e., the "degradome") in a preclinical model of fibrosis resolution. Fibrosis was induced by 4 weeks carbon tetrachloride (CCl4) exposure, and recovery was monitored for an additional 4 weeks. Some mice were treated with daily MMP12 inhibitor (MMP408) during the resolution phase. Liver injury and fibrosis was monitored by clinical chemistry, histology and gene expression. The release of degraded ECM peptides in the plasma was analyzed using by 1D-LC-MS/MS, coupled with PEAKS Studio (v10) peptide identification. Hepatic fibrosis and liver injury rapidly resolved in this mouse model. However, some collagen fibrils were still present 28d after cessation of CCl4. Despite this persistent collagen presence, expression of canonical markers of fibrosis were also normalized. The inhibition of MMP12 dramatically delayed fibrosis resolution under these conditions. LC-MS/MS analysis identified that several proteins were being degraded even at late stages of fibrosis resolution. Calpains 1/2 were identified as potential new proteases involved in fibrosis resolution. CONCLUSION. The results of this study indicate that remodeling of the liver during recovery from fibrosis is a complex and highly coordinated process that extends well beyond the degradation of the collagenous scar. These results also indicate that analysis of the plasma degradome may yield new insight into the mechanisms of fibrosis recovery, and by extension, new "theragnostic" targets. Lastly, a novel potential role for calpain activation in the degradation and turnover of proteins was identified.

pathology↗