Letter: gender‐associated cell‐free microRNA profiles in non‐alcoholic fatty liver disease

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Sirs; The study by Schwimmer et al. suggested the existence of a gender phenomenon in non-alcoholic fatty liver disease (NAFLD).1 First, the majority of children diagnosed with NAFLD were male. Second, NAFLD boys had significantly higher levels of serum alanine aminotransferases (ALT) than NAFLD girls. This ALT trend, however, was also seen in non-NAFLD children who were obese and overweight. Therefore, ALT alone was likely inadequate, if at all involved, in explaining the biology underlying the gender-skewed prevalence of NAFLD in their study and others.2 We have identified miRNA profiles in fasting serum from NAFLD patients (n = 5) recruited to the National Institutes of Health (NIH) Clinical Research Center between January 2009 and December 2012, compared with age and race matched controls with no NAFLD (n=5) using nCounter® (Nanostring). Male NAFLD patients also had significantly (P < 0.05) upregulated expressions of the hsa-miR-432-5p, hsa-miR-578, and hsa-miR-155-5p compared to female NAFLD patients (See Figure 1). The hsa-miR-432-5p and hsa-miR-301b levels were significantly (P < 0.05) higher in NAFLD male patients compared to male controls. In contrast, female NAFLD patients did not have significantly different miRNA levels compared to female controls. Thus, our pilot study showed empirical evidence for a male NAFLD-associated miRNA profile. Figure 1 MicroRNA Expressions in Male NAFLD versus Female NAFLD Patients. The male NAFLD-associated miRNA species found above are linked to inflammatory cytokines.3 Our findings also add to the literature suggesting the intriguing involvement of oestrogen and endocrine/metabolic signaling in NAFLD pathogenesis. In mice, oestrogen withdrawal leads to alterations in the peroxisome proliferator-activated receptor (PPAR) genes, which are the predicted targets of hsa-miR-142, which in turn is a target of hsa-miR-155. 4,5,6 We suggest that these male NAFLD miRNA profiles provide a starting point not only for the development of biomarkers for male NAFLD screening, but also for understanding the molecular basis of a gender-unique NAFLD pathogenesis.