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). 01/2012; 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 Bookmarks
 · 
107 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is a need for better biomarkers of drug-induced liver injury (DILI) to guide risk assessment and patient management. Over the past 3 years, both animal and clinical studies have provided proof-of-concept data showing that a subset of miRNAs appear to offer unique advantages over the conventional DILI biomarkers, such as enhanced sensitivity and specificity, reduced inter-individual variations, the potential to differentiate lethal and nonlethal liver injury, and the ability to reflect the patterns and even the etiology of liver injury. Notably, many studies have demonstrated that level of miR-122, a liver-enriched miRNA accounting for approximately 70% of total hepatic miRNAs, was increased many fold in the blood when DILI occurred. However, currently available data are predominantly based on animal models and not human samples. Due to the lack of a standard quantification method for miRNAs and confirmatory studies using a comprehensive list of drugs and patients, the true value of all reported miRNA biomarkers remains to be carefully assessed. An outstanding challenge is to examine if miRNAs are also useful for idiosyncratic DILI, which constitutes the major part of clinical DILI cases but generally cannot be recapitulated in traditional animal models or in clinical trials (the latter due to its relative rarity).
    Biomarkers in Medicine 04/2013; 7(2):307-15. · 3.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Circulating microRNAs (miRNAs) are receiving attention as potential biomarkers of various diseases, including cancers, chronic obstructive pulmonary disease, and cardiovascular disease. However, it is unknown whether the levels of circulating miRNAs in a healthy subject might vary with external factors in daily life. In this study, we investigated whether cigarette smoking, a habit that has spread throughout the world and is a risk factor for various diseases, affects plasma miRNA profiles. We determined the profiles of 11 smokers and 7 non-smokers by TaqMan MicroRNA array analysis. A larger number of miRNAs were detected in smokers than in non-smokers, and the plasma levels of two thirds of the detected miRNAs (43 miRNAs) were significantly higher in smokers than in non-smokers. A principal component analysis of the plasma miRNA profiles clearly separated smokers and non-smokers. Twenty-four of the miRNAs were previously reported to be potential biomarkers of disease, suggesting the possibility that smoking status might interfere with the diagnosis of disease. Interestingly, we found that quitting smoking altered the plasma miRNA profiles to resemble those of non-smokers. These results suggested that the differences in the plasma miRNA profiles between smokers and non-smokers could be attributed to cigarette smoking. In addition, we found that an acute exposure of ex-smokers to cigarette smoke (smoking one cigarette) did not cause a dramatic change in the plasma miRNA profile. In conclusion, we found that repeated cigarette smoking substantially alters the plasma miRNA profile, interfering with the diagnosis of disease or signaling potential smoking-related diseases.
    Toxicology and Applied Pharmacology 05/2013; · 3.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Plasma derived miRNAs are being used as biomarkers and have been associated with human liver disease and function including fibrosis, inflammation, and drug induced liver injury. They may also be biomarkers of the drug metabolism function of the liver. In order for plasma miRNA to function as a clinical biomarker, predictable variability is necessary during processing from whole blood to plasma. The current study evaluated miRNAs variability in whole blood stored for 0.5, 1, 2, 4, 8, and 12 hrs following the blood draw under clinic conditions (room temperature) prior to the separation of the plasma. Four healthy volunteer subjects were recruited. All subjects' blood was collected twice. Mir-16 and mir-223 were evaluated because many studies have shown them to be reliably present in the plasma and useful for normalization. MiRNA concentrations were measured by real-time PCR. The coefficient of variability of the CT values for subjects for miR-223 and miR-16 ranged from ~3.6 to 6.8% and ~1.48 to 4.1% respectively over the 12 hour incubation. A second blood collection was performed to determine interday variability. The coefficient of variance from the initial blood draw compared to the final blood draw for each subject ranged from 0.42 to 7.9% for miR-16 and 1.7 to 8.3% for miR-223, indicating that these miRNAs have limited interday variability. We conclude that plasma miR-16 or miR-223 concentrations are stable in whole blood at room temperature for up to at least 12 hours.
    Drug metabolism and disposition: the biological fate of chemicals 07/2013; · 3.74 Impact Factor

Full-text (2 Sources)

View
49 Downloads
Available from
May 16, 2014