Sex differences in the progression from NAFL to NASH: a functional meta-analysis of transcriptomic studies

Background & aims Sex differences in non-alcoholic fatty liver disease (NAFLD) are well known and yet, most of the studies available in the literature do not include this factor when analysing the data. Here we present a functional meta-analysis of NAFLD studies to detect the molecular mechanisms involved in its progression, distinguishing any differences relative to patient sex. Methods: We systematically reviewed the Gene Expression Omnibus (GEO) database functional Gene Ontology (GO) terms detailed in transcriptomic studies, following the PRISMA statement guidelines. For each study, we compared the progression from steatosis (NAFL) to steatohepatitis (NASH) in premenopausal women and men using a dual strategy: a gene-set analysis and a pathway activity analysis. The functional results of all the studies were integrated in a meta-analysis used to detect functions that were differentially affected in these groups, according to these two methods. Results: A total of 105 abstracts were reviewed and 7 studies, which included 624 patients, were finally analysed. The meta-analyses highlighted significant functions in both sexes. In premenopausal women, the overrepresented functions referred to DNA regulation, vinculin binding, interleukin 2 (IL-2) responses, negative regulation of neuronal death, and the transport of ions and cations. In men, they referred to the negative regulation of IL-6 and the establishment of planar polarity involved in neural tube closure. Conclusions: Our meta-analysis of this transcriptomic data provides a powerful approach to identify sex differences in the progression from NAFL to NASH. We detected relevant biological functions and molecular terms that were affected differently between premenopausal women and men. Changes in the immune responsiveness between men and women with NAFLD suggested that women have a more immune tolerant milieu while men have an impaired liver regenerative response. These results open the door to more pathophysiological studies into the differential role of IL-2 and IL-6 in NAFLD, and eventually to personalised treatments for this disease. Lay summary: Progression from NAFL to NASH differently affects cellular functions in women and men. Here we systematically reviewed publicly available transcriptomic data and then performed a meta-analysis to find these affected functions. Thus, we identified 13 biological functions implicated in the progression of NAFLD that were differentially affected by sex.