Exposição prolongada à dieta rica em sacarose suprime vias adaptativas ao estresse do retículo endoplasmático em hepatócitos e potencializa a lipogênese de novo em camundongos

Abstract

Non-alcoholic fatty liver disease (NAFLD) is defined as the abnormal triglyceride accumulation into hepatocytes (steatosis) in the absence of chronic alcoholism. Upon unsolved stress, this steatosis evolve to inflammatory and fibrotic pattern, predisposing to worsen hepatic diseases. In the context, the present study sought to investigate the role of disrupted lipogenesis and endoplasmic reticulum (ER) stress sucrose intakeinduced to NAFLD development. For this, post-weaned Swiss mice were fed a highsucrose diet (HSD) for 30, 60 and 90 days and compared to control. Metabolic syndrome (MetS) development, liver fat content, histological analysis and hepatic gene expressions of lipogenesis and ER stress were assessed. Exposure to HSD promoted progressive metabolic disturbances in a time-dependent manner leading to full establishment of MetS upon 60 days, characterized by central obesity, hyperglicemia, dyslipidemia and insulin resistance. Moreover, these animals presented increased fat liver content and microvesicular steatosis. After 30 days of nutritional intervention were found a balance between fatty acids synthesis (ChREBP and SCD1) and oxidation (PPARα) as well as an UPR-adaptive pathways featured by gene expressions of UPR sensors (IRE1α, PERK and ATF6), chaperones (GRP78 and PDI A1) and antioxidant defense transcription factor (NRF2). Whereas since 60 days were marked by higher gene expression of lipogenesis transcription factors (ChREBP and SREBP-1c), exponential raise of fatty acids synthesis (SCD1), and ER stress characterized by an apoptotic (CHOP) pattern. In summary, our results demonstrated that metabolic changes induced by sucrose consumption promoted a disregulation of de novo lipogenesis (DNL) and activation of adaptive pathways in response to ER stress, however with diet maintainence, it was observed failure of these pathways followed by an exacerbated DNL activation, which lead to increased fat accumulation in hepatocytes and subsequent NAFLD.