Article

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

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
PLoS ONE (Impact Factor: 3.53). 02/2012; 7(2):e30250. DOI: 10.1371/journal.pone.0030250
Source: PubMed

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.

0 Followers
 · 
127 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis (NASH), which can progress to fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma. Despite being one of the most common chronic liver diseases, NAFLD pathogenesis remains largely unknown. In this review, we discuss key molecular mechanisms involved in NAFLD development and progression, focusing on the emerging role of microRNAs (miRNAs). NAFLD is intrinsically related with obesity and the metabolic syndrome. Changes in lipid metabolism increase free fatty acids in blood that in turn induces peripheral insulin resistance and increases oxidative and endoplasmic reticulum stress. Although not yet considered in the diagnosis of NAFLD, recent reports also reinforce the crucial role of apoptosis in disease progression, through activation of either death receptor or mitochondrial pathways and p53. In addition, the role of gut microbiota and the gut-liver axis has been recently associated with NAFLD. Finally, there is an accumulating and growing body of evidence supporting the role of miRNAs in NAFLD pathogenesis and progression, and hinting at their use as biomarkers or therapeutic tools. The ultimate goal is to review different molecular pathways that may underlie NAFLD pathogenesis in the hope of finding targets for new and efficient therapeutic interventions.This article is protected by copyright. All rights reserved.
    FEBS Journal 04/2014; DOI:10.1111/febs.12806 · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracellular microRNAs (miRNAs) have emerged as novel biomarkers (BMs) for various pathological states. To evaluate whether urinary miRNAs could serve as biomarkers for drug-induced kidney injury, we performed a nephrotoxicity study in rats with cisplatin (Cp) which is known to induce renal proximal tubular lesions in several species. Male Wistar rats were treated with a single dose of Cp (0, 1 and 3mg/kg) and urine was collected on days 3, 5, 8, 15 and 26 for measurement of several biomarkers and for RNA isolation. MiRNA profiling experiments with urine samples derived from the 3mg/kg Cp dosed animals, identified 136 miRNAs significantly increased in urine 3 and 5 days after Cp administration. 18 miRNAs with distinct time-dependent profiles were further analyzed using specific miRNA assays and absolute quantification. We observed >20-fold changes for 11 of these 18 miRNAs measured in profiling experiments, and confirmed their direction of change and time course profile by absolute quantification. Furthermore we found mechanistic links between several miRNAs and simultaneously measured mRNAs in the kidney after Cp administration. These were associated with pathways suggested to be involved in Cp-induced nephrotoxicity including a DNA damage response, apoptosis, and cell cycle regulation. Overall our results indicate that miRNAs measured in urine may serve as BMs for nephrotoxicity in rats.
    Toxicology 05/2014; DOI:10.1016/j.tox.2014.05.005 · 3.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: The definitive standard for the diagnosis of nonalcoholic fatty liver disease (NAFLD) is clinico-pathological correlation, but frequently the only laboratory abnormality is an elevation of serum aminotransferases. Objective: This has resulted in the search for more specific laboratory biomarkers. Methods: The literature was searched for novel plasma/serum markers of NAFLD. Results: Studies reviewed here included histologically-confirmed patients presenting some stage of NAFLD and monitored one or more novel serum/plasma biomarkers. Conclusion: The most promising application of some of these novel biomarkers for the detection and quantification of NAFLD and particularly NASH appears to be in the combination of several into diagnostic panels.
    Biomarkers 09/2014; 19(7). DOI:10.3109/1354750X.2014.958535 · 2.52 Impact Factor

Full-text (3 Sources)

Download
71 Downloads
Available from
May 16, 2014