MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period

Tarana Arman; J. Allen Baron; Katherine D. Lynch; Laura A. White; Johnny Aldan; John D. Clarke

doi:10.1016/j.tox.2021.153021

Back

MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period

Journal article

Open access

Peer reviewed

MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period

Tarana Arman, J. Allen Baron, Katherine D. Lynch, Laura A. White, Johnny Aldan and John D. Clarke

Toxicology (Amsterdam), Vol.464, pp.153021-153021

12/01/2021

DOI: https://doi.org/10.1016/j.tox.2021.153021

PMID: 34740672

Files and links (2)

pdf

1-s2.0-S0300483X2100343716.44 MBDownload View

CC BY-NC-ND V4.0, Open Access

url

https://doi.org/10.1016/j.tox.2021.153021View

Published (Version of record) Open

Abstract

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Toxicology

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 mu g/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.

Metrics

Details

Title: MCLR-elicited hepatic fibrosis and carcinogenic gene expression changes persist in rats with diet-induced nonalcoholic steatohepatitis through a 4-week recovery period
Creators: Tarana Arman - Washington State University Spokane
J. Allen Baron - Washington State University Spokane
Katherine D. Lynch - Washington State Univ, Dept Pharmaceut Sci, Spokane, WA 99202 USA
Laura A. White - Washington State University, Department of Veterinary Microbiology and Pathology
Johnny Aldan - Washington State University Spokane
John D. Clarke - Washington State University, Department of Pharmaceutical Sciences
Publication Details: Toxicology (Amsterdam), Vol.464, pp.153021-153021
Academic Unit: Department of Pharmaceutical Sciences
Publisher: Elsevier
Number of pages: 17
Grant note: R00ES024455 / National Institute of Environmental Health Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) Washington State University
Identifiers: 99901181236601842
Language: English
Resource Type: Journal article