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We appreciate the feedback from the Sookoian group. Indeed, previous studies have demonstrated that plasma levels of miRNA-122 were increased in patients with nonalcoholic fatty liver disease (NAFLD).1 It was proposed by Pirola et al.2 that circulating miRNA-122, a marker of liver disease/damage, could also be used to predict the risk for cardiovascular disease in patients with NAFLD. A gene variant in the 3′ untranslated region of human L-arginine transporter SLC7A1, which is associated with hypertension, also contained an miRNA-122 binding site, and therefore the authors suggest that circulating miRNA-122 might be a bridge between metabolic signaling and cardiovascular disease.

It is well known that miRNA-122 regulates a broad array of genes involved in fatty acid and cholesterol metabolism (e.g, FASN, ACLY, ACC, DGATS, AGPATS, HMGCR). Recent studies suggest that a deficiency of miRNA-122 in mice (germ line and hepatocyte-specific) results in hepatosteatosis, hepatitis, and hepatocellular carcinoma.3 Furthermore, miRNA-122 also regulates mitochondrial metabolism and tumor suppressor genes, and loss of miRNA-122 leads to hepatocellular carcinoma.3, 4 Given the multifactorial role of miRNA-122 in liver homeostasis, it might not be surprising that miRNA-122 could be a potential link between metabolic disorders and cardiovascular disease. Nevertheless, the notion that circulating miRNAs can modulate genes in a distant organ and/or mediate the disease has to be thoroughly investigated. To date, studies are very limited on the functional relevance of circulating miRNAs in vivo. Several principal questions still remain unanswered, such as the origin of circulating miRNAs (i.e., cells versus organs), their specificity, their in vivo biodistribution, and their turnover.

Remarkably, a recent study demonstrated the induction of plasma miRNA-122 in an ischemic porcine cardiogenic shock model.5 It is most likely that liver ischemia triggered by cardiogenic shock resulted in the release of miRNA-122 to the circulation. However, this possibility was not explored. Further studies are warranted to examine the circulating miRNA in scenarios where multiple organs are affected.

In conclusion, we cautiously support the hypothesis that circulating miRNAs may have paracrine effects extending to organs other than the organ of origin and thus the ability to modulate genes at distant organs. However, due to the lack of sufficient data on the functional relevance of circulating miRNAs, this remains a speculation at this time.

Gyongyi Szabo M.D., Ph.D.*, Shashi Bala Ph.D.*, * Department of Medicine, University of Massachusetts Medical School, Worcester, MA.

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