Downregulation of microRNA-451 in non-alcoholic steatohepatitis inhibits fatty acid-induced proinflammatory cytokine production through the AMPK/AKT pathway

Abstract

Mechanisms associated with the progression of non-alcoholic fatty liver disease (NAFLD) remain unclear. We attempted to identify the pattern of altered gene expression at different time points in a high fat diet (HFD)-induced NAFLD mouse model. The early up-regulated genes are mainly involved in the innate immune responses, while the late up-regulated genes represent the inflammation processes. Although recent studies have shown that microRNAs play important roles in hepatic metabolic functions, the pivotal role of microRNAs in the progression of NAFLD is not fully understood. We investigated the functions of miR-451, which was identified as a target gene in the inflammatory process in NAFLD. miR-451 expression was significantly decreased in the palmitate (PA)-exposed HepG2 cells and in liver tissues of HFD-induced non-alcoholic steatohepatitis (NASH) mice. Its decreased expressions were also observed in liver specimens of NASH patients. In vitro analysis of the effect of miR-451 on proinflammatory cytokine provided evidence for negative regulation of PA-induced interleukin (IL)-8 and tumor necrosis factor-alpha (TNF-α) production. Furthermore, miR-451 over-expression inhibited translocation of the PA-induced NF-κB p65 subunit into the nucleus. Our result showed that Cab39 is a direct target of miRNA-451 in steatotic cells. Further study showed that AMPK activated through Cab39 inhibits NF-κB transactivation induced in steatotic HepG2 cells. miR-451 over-expression in steatotic cells significantly suppressed PA-induced inflammatory cytokine. These results provide new insights into the negative regulation of miR-451 in fatty acid-induced inflammation via the AMPK/AKT pathway and demonstrate potential therapeutic applications for miR-451 in preventing the progression from simple steatosis to severely advanced liver disease.

Deregulated hepatic microRNAs underlie the association between non‐alcoholic fatty liver disease and coronary artery disease

“…It has been published that several miRNAs regulate cholesterol homoeostasis and fatty acid metabolism and are implicated in CAD, NAFLD and NASH . Indeed, mice with diet‐induced NASH exhibited a characteristic aberrant hepatic miRNAs pattern similar to our results, namely overexpressed miR‐34a, miR‐155, miR‐200b and miR‐221 and downexpressed miR‐29c, miR‐122, miR‐192 and miR‐203 .…”

The Expression of Nuclear Transcription Factor Kappa B (NF-κB) in the Case of Critically Ill Polytrauma Patients with Sepsis and Its Interactions with microRNAs

“…Further, it was clearly evident from his study that there exists a significant correlation between intense expression of microRNA-155, microRNA-872 and microRNA-183 in the cases having rise in pro-inflammatory and pro-oxidative status (Hulsmans et al 2011). A similar study was performed by Hur et al, who confirmed the implication of microRNA-451 in augmenting the inflammatory state by increasing the production of pro-inflammatory molecules (Hur et al 2015). Moreover, Hulsmans et al, illustrated that a series of redox disturbances exists due to lipid peroxidation.…”

Rhein lysinate decreases inflammation and adipose infiltration in KK/HlJ diabetic mice with non-alcoholic fatty liver disease

“…Second, NF-jB stimulates the immune response, specifically through the production of pro-inflammatory cytokines (Wang et al 2009). Inflammation mediated by NF-jB plays a critical role in the pathogenesis of NAFLD (He et al 2015;Hur et al 2015). In the present study, we observed that TNF-a indirectly induced hepatocyte injury and hepatic adipose infiltration through the TNF-a/NF-jB signaling pathway.…”