Plasma MicroRNA Profiles in Rat Models of Hepatocellular Injury, Cholestasis, and Steatosis

Abstract

MicroRNAs (miRNAs) are small RNA molecules that function to modulate the expression of target genes, playing important roles in a wide range of physiological and pathological processes. The miRNAs in body fluids have received considerable attention as potential biomarkers of various diseases. In this study, we compared the changes of the plasma miRNA expressions by acute liver injury (hepatocellular injury or cholestasis) and chronic liver injury (steatosis, steatohepatitis and fibrosis) using rat models made by the administration of chemicals or special diets. Using miRNA array analysis, we found that the levels of a large number of miRNAs (121–317 miRNAs) were increased over 2-fold and the levels of a small number of miRNAs (6–35 miRNAs) were decreased below 0.5-fold in all models except in a model of cholestasis caused by bile duct ligation. Interestingly, the expression profiles were different between the models, and the hierarchical clustering analysis discriminated between the acute and chronic liver injuries. In addition, miRNAs whose expressions were typically changed in each type of liver injury could be specified. It is notable that, in acute liver injury models, the plasma level of miR-122, the most abundant miRNA in the liver, was more quickly and dramatically increased than the plasma aminotransferase level, reflecting the extent of hepatocellular injury. This study demonstrated that the plasma miRNA profiles could reflect the types of liver injury (e.g. acute/chronic liver injury or hepatocellular injury/cholestasis/steatosis/steatohepatitis/fibrosis) and identified the miRNAs that could be specific and sensitive biomarkers of liver injury.

Expression Variability of Absorption, Distribution, Metabolism, Excretion–Related MicroRNAs in Human Liver: Influence of Nongenetic Factors and Association with Gene Expression

“…This result remained significant after correction for multiple testing and in a multivariate model considering seven factors as covariates (see Materials and Methods; Supplemental Table 3). MiR-130b was observed before to be downregulated in plasma of bile-duct ligationinduced cholestatic rats (Yamaura et al, 2012) and has been suggested as potential marker for hepatocellular carcinoma (Li et al, 2011). We also found increased expression of miR-21 in livers from donors with elevated CRP, a well investigated miRNA that plays a crucial role in many biologic and pathologic processes including inflammation (Kumarswamy et al, 2011).…”

“…Although large systematic studies have been performed to compare tissue-specific expression profiles of miRNAs (Barad et al, 2004;Landgraf et al, 2007), interindividual variation of expression was rarely studied, and most data on human liver expression have been obtained in context of hepatocellular carcinoma (Murakami et al, 2006;Jiang et al, 2008). In rat models, however, studies suggested that miRNA expression can also be affected by acute and chronic hepatocellular injuries (Yamaura et al, 2012).…”

Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects

“…Immediately, total RNA was isolated from 600 µl of plasma using the mirVana PARIS kit as described previously (Yamaura et al, 2012).…”

MicroRNA-145 Post-transcriptionally Regulates the Expression and Function of P-glycoprotein in Intestinal Epithelial Cells

“…MiRNA post-transcriptionally regulates gene expression by binding to the 39-untranslated region (UTR) of target mRNA to repress its translation or regulate its degradation (Kim, 2005;Filipowicz et al, 2008). Recent studies have demonstrated that the expression patterns of hepatic miRNAs are altered in various liver diseases, such as liver I/R injury ), hepatitis C (Cermelli et al, 2011), hepatocellular carcinoma (Budhu et al, 2008), and toxic-induced liver injury (Yamaura et al, 2012). These studies also indicated that miRNAs play important roles in physiologic and pathologic processes in liver diseases.…”