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To the Editor:

We read with great interest the article by Bala et al. about the role of circulating microRNAs (miRNAs) as markers of alcohol- and acetaminophen-induced liver damage in a mouse model; the investigators concluded that circulating miR-122 and miR-155 may serve as biomarkers of liver injury and inflammation, respectively.1

The concept that miRNAs in serum and plasma are powerful potential biomarkers for liver diseases has expanded very quickly in recent years, and the role of circulating miR-122 in predicting liver damage has been replicated in liver diseases of different etiologies, including human nonalcoholic fatty liver disease (NAFLD).2 In fact, we evaluated the circulating expression of a panel of 84 miRNAs in serum of patients with NAFLD proven through biopsy in a case-control design, and we observed that miR-122 was significantly up-regulated in NAFLD patients, compared to control subjects, and the fold increase was strongly related to the disease severity (NASH versus simple steatosis 3.14 and versus control subjects 7.2, fold change). Thus, we agree that circulating miR-122 is a robust biomarker for predicting NAFLD progression and perhaps is able to solve the dilemma of how useful are aminotransferases to decide patients' monitoring and liver biopsy indication because its performance seems to be much better.1, 2

Certainly, the role of circulating miRNAs in clinical scenarios is not restricted to disease monitoring. miRNAs circulate in the bloodstream and are taken up by distant cells; therefore, they have the enormous potential of regulating gene expression simultaneously in different tissues and cells like a truly new endocrine system, and, for example, miR-122 may regulate the expression of more than 170 highly interacting genes (Fig. 1).

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Figure 1. Functional association analysis of genetic interactions among the 172 conserved gene targets of human miR-122. Prediction of biological targets of miR-122 was performed by the bioinformatics resource, TargetScan (http://www.targetscan.org), by searching for the presence of conserved 8- and 7-mer sites that match its seed region; the gene-interaction network was analyzed by the bioinformatics resource, GenMANIA (http://www.genemania.org).

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In this scenario, we provide some preliminary evidence that circulating miR-122 could be also regarded as a powerful biomarker for cardiovascular disease (CVD) in patients with NAFLD. For instance, we explored, in a case-control study of 300 individuals with NAFLD, a gene variant (rs41318021) in the 3′-UTR (untranslated region) of human L-arginine transporter SLC7A1, which was associated with genetic predisposition to essential hypertension. The 3′-UTR of human SLC7A1 contains a predicted miR-122-binding site that may play a role in controlling gene expression.3 Interestingly, we found that, in patients with NAFLD, rs41318021 was significantly associated with arterial systolic and diastolic hypertension (odds ratio [OR], 2.057; 95% confidence interval [CI]: 1.279-3.294; P < 0.000001) or isolated diastolic hypertension (OR, 2.147; 95% CI: 1.245-3.702; P < 0.00075), even after adjusting for age and body mass index.

In conclusion, we suggest that circulating miR-122 is not only useful in predicting liver damage, but might integrate metabolic signaling in a putative “endocrine” fashion to mediate CVD. Hence, in patients with NAFLD, circulating miRNAs can be explored for improving diagnosis of liver injury and population screening of CVD.

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