Sex differences in non-alcoholic fatty liver disease: hints for future management of the disease

Non-alcoholic fatty liver disease (NAFLD) remains a major cause of chronic liver disease worldwide. Despite extensive studies, the heterogeneity of the risk factors as well as different disease mechanisms complicate the goals toward effective diagnosis and management. Recently, it has been shown that sex differences play a role in the prevalence and progression of NAFLD. In vitro, in vivo, and clinical studies revealed that the lower prevalence of NAFLD in premenopausal as compared to postmenopausal women and men is mainly due to the protective effects of estrogen and body fat distribution. It has been also described that males and females present differential pathogenic features in terms of biochemical profiles and histological characteristics. However, the exact molecular mechanisms for the gender differences that exist in the pathogenesis of NAFLD are still elusive. Lipogenesis, oxidative stress, and inflammation play a key role in the progression of NAFLD. For NAFLD, only a few studies characterized these mechanisms at the molecular level. Therefore, we aim to review the reported differential molecular mechanisms that trigger such different pathogenesis in both sexes. Differences in lipid metabolism, glucose homeostasis, oxidative stress, inflammation, and fibrosis were discussed based on the evidence reported in recent publications. In conclusion, with this review, we hope to provide a new perspective for the development of future practice guidelines as well as a new avenue for the management of the disease

Association of Circulating Serum miR-34a and miR-122 with Dyslipidemia among Patients with Non-Alcoholic Fatty Liver Disease

<div><p>Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of diseases from simple steatosis to non-alcoholic steatohepatitis, with approximately 20% risk of progressing to fibrosis and cirrhosis. The aim of this study was to compare the relative expression levels of circulating miR-21, miR-34a, miR-122, miR-125b and miR-375 between healthy controls and NAFLD patients, and to assess the feasibility of microRNAs as potential biomarkers for NAFLD. A cross-sectional study was conducted to evaluate circulating serum miRNAs as potential diagnostic markers for NAFLD. Twenty-eight clinically diagnosed and histologically-confirmed NAFLD patients, as well as 36 healthy controls were enrolled in this study. The relative expression of serum microRNAs were calculated using the comparative cycle threshold with spiked-in <i>C</i>. <i>elegans</i> miR-39 as exogenous internal control. Serum levels of miR-34a and miR-122 were significantly higher in NAFLD patients than in healthy controls (<i>P</i> = <0.0001). Positive correlations were observed between serum miR-34a with very low density lipoprotein cholesterol (VLDL-C) and triglyceride levels. However, the expression levels of miR-34a and miR-122 did not correlate with the histological features of NAFLD. Interestingly, receiver operating characteristic (ROC) curve analysis revealed that miR-34a and miR-122 are potential markers for discriminating NAFLD patients from healthy controls with an area under the curve (AUC) values of 0.781 and 0.858, respectively. Serum levels of miR-34a and miR-122 were found to be significantly higher among NAFLD patients, and were positively correlated with VLDL-C and triglyceride levels. Thus, circulating miR-34a and miR-122 can be used as potential biomarkers for discriminating NAFLD patients from healthy controls. Larger cohorts are required to validate the utility of miR-34a and miR-122 in monitoring liver injury.</p></div

Diagnostic performance of serum miR-34a, miR-122 and ALT in healthy controls and NAFLD patients.

<p>Diagnostic performance of serum miR-34a, miR-122 and ALT in healthy controls and NAFLD patients.</p

Up-regulation of serum miR-34a and miR-122 in NAFLD patients.

<p>Serum expression levels of miR-34a and miR-122 were measured in healthy controls and NAFLD patients. The relative expression levels were normalized to synthetic spike-in <i>C</i>. <i>elegans</i> miR-39. The <i>P</i> value was calculated according to Mann-Whitney U test. The horizontal lines indicate the medians.</p

ROC curve analysis for serum miR-34a, miR-122 and ALT.

<p>The AUC for serum miR-34a, miR-122 and ALT are 0.781, 0.858 and 0.832, respectively.</p

Relative expression of serum miR-34a and miR-122 among healthy controls and NAFLD patients according to stage of fibrosis and combined stages of fibrosis.

<p>The <i>P</i> values were calculated according to Kruskal-Wallis test with Dunn’s multiple comparison post-test. In the boxplots, the vertical lines indicate the range and the horizontal boundaries of the boxes represent the first and third quartile. The lines inside the boxes denote the medians. * p>0.01–0.05; ** p = 0.001–0.01; *** p<0.001.</p

Relative expression of serum miR-34a and miR-122 among healthy controls and NAFLD patients at various degree of liver steatosis.

<p>The <i>P</i> values were calculated according to Kruskal-Wallis test with Dunn’s multiple comparison post-test. In the boxplots, the vertical lines indicate the range and the horizontal boundaries of the boxes represent the first and third quartile. The lines inside the boxes denote the medians. * p>0.01–0.05; ** p = 0.001–0.01; *** p<0.001.</p

Relative expression of serum miR-34a and miR-122 among healthy controls and NAFLD patients at various degree of inflammation.

<p>The <i>P</i> values were calculated according to Kruskal-Wallis test with Dunn’s multiple comparison post-test. In the boxplots, the vertical lines indicate the range and the horizontal boundaries of the boxes represent the first and third quartile. The lines inside the boxes denote the medians. * p>0.01–0.05; ** p = 0.001–0.01; *** p<0.001.</p

Demographic and clinical characteristics of healthy controls and NAFLD patients.

<p>Demographic and clinical characteristics of healthy controls and NAFLD patients.</p

Relative expression levels of serum miR-34a, miR122 and histological features of NAFLD patients.

<p>Relative expression levels of serum miR-34a, miR122 and histological features of NAFLD patients.</p