The Potential Protective Role of RUNX1 in Nonalcoholic Fatty Liver Disease

Abstract

The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA hepatic and jejunal abundance in women with morbid obesity (MO) and NAFLD. RUNX1, lipid metabolism-related genes, and TLRs in women with MO and normal liver (NL, n = 28), NAFLD (n = 41) (simple steatosis (SS, n = 24), or NASH (n = 17)) were analyzed by RT-qPCR. The RUNX1 hepatic expression was higher in SS than in NL or NASH, as likewise confirmed by immunohistochemistry. An increased expression of hepatic FAS was found in NAFLD. Hepatic RUNX1 correlated positively with FAS. There were no significant differences in the jejunum RUNX1 expressions in the different groups. Jejunal FXR expression was lower in NASH than in NL, while the TLR9 expression increased as NAFLD progressed. Jejunal RUNX1 correlated positively with jejunal PPARγ, TLR4, and TLR5. In summary, the hepatic expression of RUNX1 seems to be involved in the first steps of the NAFLD process; however, in NASH, it seems to be downregulated. Our findings provide important insights into the role of RUNX1 in the context of NAFLD/NASH, suggesting a protective role.

Identification of the Potential Molecular Mechanisms Linking RUNX1 Activity with Nonalcoholic Fatty Liver Disease, by Means of Systems Biology

“…In this regard, this result matches with Kaur et al, who reported a relevant association between RUNX1 expression and fibrosis and inflammation, two of the main NASH parameters [ 20 ]. However, this result contradicts our previous reported hypothesis about the potential protective role of RUNX1 in early stages of NAFLD [ 21 ]; in contrast, our current result has shown a low or medium intensity relationship with SS-related parameters. Given that our ANN approach provides the probability of functional relationship–regardless of the activity status (up or downregulation)–and the current conflicting results in the literature, further studies in humans or in vivo are required to clarify these contradictions, although the current available evidence clearly supports an involvement, either by presence or absence, of RUNX1 in NAHLD and NASH.…”

“…In this sense, these authors suggested that RUNX1 is a tumour suppressing factor that inhibits angiogenesis [ 33 ]. Regarding our previous study, we reported that the mRNA and protein expression of RUNX1 in liver seems to be involved in first steps of NAFLD with a proangiogenic-repairing role; meanwhile, RUNX1 appears to be downregulated in the NASH stage [ 21 ]. Since these disagreements, an exhaustive study of the relationship between RUNX1 MoA and NAFLD/NASH pathogenesis need to be performed to clarify this issue.…”

“…It was demonstrated that proangiogenic factors have an early function in NAFLD progression from SS to NASH since proangiogenic treatments reduce not only inflammation but also steatosis [ 52 ]. In this regard, RUNX1, a pivotal regulator of hematopoiesis and angiogenesis [ 12 , 53 ], could be activated in order to repair the liver damage in early stages of NAFLD [ 21 , 54 ]. In contrast, RUNX1 activates target genes involved in lipotoxicity [ 55 , 56 , 57 , 58 ] such as CEBPB [ 59 ] and Cyclic AMP-dependent transcription factor (AT6) in a regulatory feed-back loop with the transcription factor AP-1 and JNK [ 60 ].…”

“…Thus, we previously wanted to study the role of RUNX1 mRNA and protein expression in NAFLD in a cohort of women with morbid obesity. We hypothesized that RUNX1 may play a protective role in NAFLD since its expression was enhanced in early stages of the disease and decrease along with the progression to NASH [ 21 ]. Given these controversies among our previous results and what was already known, the objective of the present work is to determine the proteins and the potential molecular mechanisms that could establish a link between the activity of RUNX1 and NAFLD pathogenesis by means of systems biology.…”

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

“…Increasing evidence demonstrated that hsa-mir-150-5p [723] and TP53 [724] have a function in diabetes mellitus, but these genes might be novel targets for NAFLD. Bertran et al [725], Yan et al [726] and Zhu et al [727] revealed that RUNX1, TP53 and AHR (aryl hydrocarbon receptor) may be the potential targets for NAFLD diagnosis and treatment. Thus, hsa-mir-33a-3p, hsa-mir-561-3p, hsa-mir-30b-3p and hsa-mir-202-3p can be novel molecular markers of NAFLD and provide new insight to improve therapeutic strategies for NAFLD complications.…”