Temporal Effects of Lipid Oversupply on Energy Metabolism and Mitochondrial Homeostasis in Hepatocytes

Obesity is closely associated with multiple metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD are susceptible to develop irreversible life-threatening diseases, however, the evolution concerning mitochondrial and metabolic alterations during NAFLD development and progression remain elusive. This study focused on uncovering the sequential events of energy metabolism and mitochondrial homeostasis of hepatocytes under the environment of lipid oversupply by in vitro and in vivo strategies. Long-chain fatty acid (FA) synthesis and lipid storage were first induced by providing hepatocytes with sufficient energy source, followed by suppressed glucose metabolic efficiency and decreased mitochondrial mass. Intriguingly, distinctive features of hepatic cancer cells in response to FA oversupply were characterized. Insulin signaling and glucose uptake were rapidly deterred while lipid β-oxidation was significantly boosted. Enhanced mitochondrial biogenesis was identified as compensatory feedback for mitochondrial dysfunction. FA-induced mitophagy, cell morphological transition and higher N-cadherin expression potentiates epithelial-mesenchymal transition (EMT) which confers the cells with higher plasticity and accelerates NAFLD progression to irreversible hepatic diseases. This study provides evidence elucidating the temporal events caused by FA oversupply, moreover, delineates the facilitative role of excess nutrients in shaping the environment for lipid-laden hepatocytes to acquire malignant traits. Given the rapidly increasing global prevalence of metabolic disorders and the heterogeneous manifestations exhibited by NAFLD during disease progression, better understanding of the sequential events caused by FA overload aids in identifying promising targets and developing tailor-made treatment protocol according to individual disease status and conditions.