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John Clarke Lab Research in Toxicities in NAFLD

Reduced hepatic recovery after MCLR toxicity in NASH

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 a risk factor for HCC. The current study investigated hepatic recovery after MCLR elicited
liver injury in pre-existing NASH. 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.