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| Status |
Public on Nov 06, 2021 |
| Title |
MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Nonalcoholic steatohepatitis (NASH) causes liver extracellular matrix (ECM) remodeling and is a risk factor for fibrosis and hepatocellular carcinoma (HCC). Microcystin-LR (MCLR) is a hepatotoxin produced by fresh-water cyanobacteria that causes a NASH-like phenotype, liver fibrosis, and is also a risk factor for HCC. The focus of the current study was to investigate and compare hepatic recovery after cessation of MCLR exposure in healthy versus NASH animals. Male Sprague-Dawley rats were fed either a control or a high fat/high cholesterol (HFHC) diet for eight weeks. Animals received either vehicle or 30 µg/kg MCLR (i.p: 2 weeks, alternate days). Animals were euthanized at one of three time points: at the completion of the MCLR exposure period and after 2 and 4 weeks of recovery. Histological staining suggested that after four weeks of recovery the MCLR-exposed HFHC group had less steatosis and more fibrosis compared to the vehicle-exposed HFHC group and MCLR-exposed control group. RNA-Seq analysis revealed dysregulation of ECM genes after MCLR exposure in both control and HFHC groups that persisted only in the HFHC groups during recovery. After 4 weeks of recovery, MCLR hepatotoxicity in pre-existing NASH persistently dysregulated genes related to cellular differentiation and HCC. These data demonstrate impaired hepatic recovery and persistent carcinogenic changes after MCLR toxicity in pre-existing NASH.
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| Overall design |
Eight-week old male Sprague Dawley rats (n=72) were purchased from Envigo and were maintained in 12 hour light and dark cycles. Animals were divided into two groups (n=36 per diet group) and fed (ad-libitum) either a control diet or HFHC diet for 8 weeks. Following 8 week diet period, animals were administered vehicle or MCLR via intraperitoneal injections every 48 hours for 2 weeks. Animals were euthanized at three recovery time points: 24 hours (0 week recovery), 2 weeks (2 week recovery) and 4 weeks (4 week recovery) (n=6 per diet and treatment group) after the last MCLR administration.
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| Contributor(s) |
Clarke JD, Baron JA, Arman T, Lynch KD |
| Citation missing |
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| Submission date |
Nov 04, 2021 |
| Last update date |
Nov 06, 2021 |
| Contact name |
John D. Clarke |
| E-mail(s) |
j.clarke@wsu.edu
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| Organization name |
Washington State University
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| Department |
Pharmaceutical Sciences
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| Lab |
Clarke Lab
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| Street address |
412 E. Spokane Falls Blvd., 412 E. Spokane Fall BLVD
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| City |
Spokane |
| State/province |
Washington |
| ZIP/Postal code |
99202 |
| Country |
USA |
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| Platforms (1) |
| GPL18694 |
Illumina HiSeq 2500 (Rattus norvegicus) |
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| Samples (72)
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| Relations |
| BioProject |
PRJNA777952 |
| SRA |
SRP344641 |
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