Abstract
Nonalcoholic steatohepatitis (NASH) is a major cause of liver fibrosis with increasing prevalence worldwide. Currently there are no approved drugs available. The development of new therapies is difficult as diagnosis and staging requires biopsies. Consequently, predictive plasma biomarkers would be useful for drug development. Here we present a multi-omics approach to characterize the molecular pathophysiology and to identify new plasma biomarkers in a choline-deficient L-amino acid-defined diet rat NASH model. We analyzed liver samples by RNA-Seq and proteomics, revealing disease relevant signatures and a high correlation between mRNA and protein changes. Comparison to human data showed an overlap of inflammatory, metabolic, and developmental pathways. Using proteomics analysis of plasma we identified mainly secreted proteins that correlate with liver RNA and protein levels. We developed a multi-dimensional attribute ranking approach integrating multi-omics data with liver histology and prior knowledge uncovering known human markers, but also novel candidates. Using regression analysis, we show that the top-ranked markers were highly predictive for fibrosis in our model and hence can serve as preclinical plasma biomarkers. Our approach presented here illustrates the power of multi-omics analyses combined with plasma proteomics and is readily applicable to human biomarker discovery.
Highlights
Nonalcoholic steatohepatitis (NASH) is a major cause of liver fibrosis with increasing prevalence worldwide
Around 10% of Nonalcoholic fatty liver disease (NAFLD) patients successively develop nonalcoholic steatohepatitis (NASH)[1], which is characterized by hepatic inflammation and fibrosis[2]
We investigated the choline-deficient L-amino acid-defined (CDAA) diet with different supplementary combinations using Wistar rats for their suitability as a preclinical NASH model[19]. From this experiment we selected the CDAA diet supplemented with 1% cholesterol for molecular profiling because it shows the most relevant phenotype
Summary
Nonalcoholic steatohepatitis (NASH) is a major cause of liver fibrosis with increasing prevalence worldwide. We present a multi-omics approach to characterize the molecular pathophysiology and to identify new plasma biomarkers in a choline-deficient L-amino acid-defined diet rat NASH model. We show that the top-ranked markers were highly predictive for fibrosis in our model and can serve as preclinical plasma biomarkers. There is a lack of studies that systematically asses the translation of the molecular changes in the diseased liver at the RNA level to changes at the liver and plasma protein level for the discovery of non-invasive biomarkers. There are several preclinical animal models for NASH established or under development[15,16,17] They differ in the way of triggering a NASH-like phenotype (obesogenic dietary, nutrient-deficient dietary, genetic, chemically induced, surgery-based) and in their ability to reflect the human etiology and histopathology[15]. Among the cholesterol supplementations tested, 1% cholesterol showed the most suitable phenotype for pharmacological testing[19]
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