Abstract
Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD.
Highlights
Non-predictive animal models may result in the clinical failure of new drugs or therapeutic approaches[8,9]
Chronic alcohol exposure has been shown to lead to liver steatosis and fibrosis in rhesus monkeys that were fed with a 7% ethanol solution and a low essential fatty acid diet for five years[13,14]
We describe the development of rhesus models with liver steatosis, alcoholic hepatitis and hepatic fibrosis
Summary
Non-predictive animal models may result in the clinical failure of new drugs or therapeutic approaches[8,9]. “humans are not 70-kg mice”, either in terms of pharmacology or toxicology[8], and suitable animal models that mimic clinical disease progression in humans are still needed. Because of their genetic, anatomical and physiological similarity to humans, nonhuman primates are essential and irreplaceable animal models in human disease research. To enable the systematic preclinical evaluation of the efficacy and safety of candidate drugs or therapies for human ALD, it is important that rhesus ALD models reflect both clinical disease progression and gene expression. To identify potential molecular signatures of disease progression and to compare gene expression patterns to those of humans with ALD, array-based mRNA analyses were conducted using animal liver tissue
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