Mechanism linking miR-18a-5p/SREBP1/PERK axis, ER stress and autophagy to the early stages of Nonalcoholic Fatty Liver Disease (NAFLD) induced by high fat diet

The global epidemic of obesity is accompanied by a rising burden of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by hepatic accumulation of lipids, causing cellular stress and hepatic injury, which ultimately leads to chronic liver disease. Abnormal lipid accumulation is associated with perturbed endoplasmic reticulum (ER) proteostasis in hepatocytes. Alteration in ER function, known as “ER stress,” is emerging as a key feature of metabolic disorders. Excess lipid exposure leads to ER stress and, conversely, ER stressors disrupt lipid metabolism. During the last years, studies on the relationship between ER stress and microRNAs (miRNAs) has burst on the scene. Based on these considerations, the aim of this study was to investigate the involvement of miR18a-5p/SREBP1/PERK pathway in ER stress and how this pathway can affect autophagy and apoptosis in early stages of NAFLD induced by high fat diet. To this purpose, male wistar rats fed on a high-fat diet for 5 weeks were been used. In addition, in order to verify the central role of the miR18a-5p/SREBP1 axis, an in-vitro model of Hep-G2 cells transfected with mimic miR-18a-5p and subsequently treated with an oleate/palmitate mixture for 24 hours were been used. The results indicated that in both the experimental models the expression of miR-18a-5p was downregulated by excess fat. This downregulation was associated with increase of SREBP1c and PERK levels, highlighting a state of ER stress. Furthermore, the activation of PERK signaling induced an increase in autophagic process, and an increase in pro-apoptotic markers and a decrease in anti-apoptotic markers level, suggesting also an induction of apoptosis. Taken together, our study reveals the involvement of miR-18a-5p/SREBP1/PERK axis in the ER stress induced by a fat diet, thus providing promising drug targets for tailored therapy in the advanced fat liver setting.